1. Field of the Invention
The present invention relates to spiroimidazolidine derivatives of the formula I 
in which E, V, W, X, R1 and R2 have the meanings indicated below. The compounds of the formula I are valuable pharmaceutical active compounds, which are suitable, for example, for the therapy and prophylaxis of inflammatory disorders, for example of rheumatoid arthritis, or of allergic disorders. The compounds of the formula I are inhibitors of the adhesion and migration of leukocytes and/or antagonists of the adhesion receptor VLA-4 belonging to the integrins group. They are generally suitable for the therapy and prophylaxis of illnesses which are caused by an undesired extent of leukocyte adhesion and/or leukocyte migration or are associated therewith or in which cell-cell or cell-matrix interactions which are based on interactions of VLA-4 receptors with their ligands play a part. The invention furthermore relates to processes for the preparation of the compounds of the formula I, their use and pharmaceutical preparations which contain compounds of the formula I.
2. Description of the Related Art
The integrins are a group of adhesion receptors which play an important part in cell-cell-binding and cell-extracellular matrix-binding processes. They have an xcex1xcex2-heterodimeric structure and exhibit a wide cellular distribution and a high extent of evolutive conservation. The integrins include, for example, the fibrinogen receptor on platelets, which interacts especially with the RGD sequence of fibrinogen, or the vitronectin receptor on osteoclasts, which interacts especially with the RGD sequence of vitronectin or of osteopontin. The integrins are divided into three major groups, the xcex22 subfamily with the representatives LFA-1, Mac-1 and p150/95, which are responsible in particular for cell-cell interactions of the immune system, and the subfamilies xcex21 and xcex23, whose representatives mainly mediate cell adhesion to components of the extracellular matrix (Ruoslahti, Annu. Rev. Biochem. 1988, 57, 375). The integrins of the xcex21 subfamily, also called VLA proteins (very late (activation) antigen), include at least six receptors which interact specifically with fibronectin, collagen and/or laminin as ligands. Within the VLA family, the integrin VLA-4 (xcex14xcex21) is atypical, insofar as it is mainly restricted to lymphoid and myeloid cells and is responsible in these for cell-cell interactions with a large number of other cells. For example, VLA-4 mediates the interaction of T and B lymphocytes with the heparin II-binding fragment of human plasma fibronectin (FN). The binding of VLA-4 with the heparin II-binding fragment of plasma fibronectin is especially based on an interaction with an LDVP sequence. In contrast to the fibrinogen or vitronectin receptor, VLA-4 is not a typical RGD-binding integrin (Kilger and Holzmann, J. Mol. Meth. 1995, 73, 347).
The leukocytes circulating in the blood normally exhibit only a low affinity for the vascular endothelial cells which line the blood vessels. Cytokines which are released from inflamed tissue cause the activation of endothelial cells and thus the expression of a large number of cell surface antigens. These include, for example, the adhesion molecules ELAM-1 (endothelial cell adhesion molecule-1; also designated as E-selectin), which, inter alia, binds neutrophils, ICAM-1 (intercellular adhesion molecule-1), which interacts with LFA-1 (leukocyte function-associated antigen 1) on leukocytes, and VCAM-1 (vascular cell adhesion molecule-1), which binds various leukocytes, inter alia lymphocytes (Osborn et al., Cell 1989, 59, 1203). VCAM-1, like ICAM-1, is a member of the immunoglobulin gene superfamily. VCAM-1 (first known as INCAM-110) was identified as an adhesion molecule that is induced on endothelial cells by inflammatory cytokines such as TNF and IL-1 and lipopolysaccharides (LPS). Elices et al. (Cell 1990, 60, 577) showed that VLA-4 and VCAM-1 form a receptor-ligand pair which mediates the adhesion of lymphocytes to activated endothelium. The binding of VCAM-1 to VLA-4 does not take place here due to an interaction of the VLA4 with an RGD sequence; this sequence is not contained in VCAM-1 (Bergelson et al., Current Biology 1995, 5, 615). VLA-4, however, also occurs on other leukocytes, and the adhesion of leukocytes other than lymphocytes is also mediated via the VCAM-1/VLA-4 adhesion mechanism. VLA-4 thus represents an individual example of a xcex21 integrin receptor which, via the ligands VCAM-1 and fibronectin, plays an important part both in cell-cell interactions and in cell-extracellular matrix interactions.
The cytokine-induced adhesion molecules play an important part in the recruitment of leukocytes into extravascular tissue regions. Leukocytes are recruited into inflammatory tissue regions by cell adhesion molecules which are expressed on the surface of endothelial cells and serve as ligands for leukocyte cell surface proteins or protein complexes (receptors) (the terms ligand and receptor can also be used vice versa). Leukocytes from the blood must first adhere to endothelial cells before they can migrate into the synovium. Since VCAM-1 binds to cells which carry the integrin VLA-4 (xcex14xcex21), such as eosinophils, T and B lymphocytes, monocytes or neutrophils, it and the VCAM-1/VLA-4 mechanism have the function of recruiting cells of this type from the blood stream into areas of infection and inflammatory foci (Elices et al., Cell 1990, 60, 577; Osborn, Cell 1990, 62, 3; Issekutz et al., J. Exp. Med. 1996, 183, 2175).
The VCAM-1/VLA-4 adhesion mechanism has been connected with a number of physiological and pathological processes. Apart from by cytokine-induced endothelium, VCAM-1 is additionally expressed, inter alia, by the following cells: myoblasts, lymphoid dendritic cells and tissue macrophages, rheumatoid synovium, cytokine-stimulated neural cells, parietal epithelial cells of the Bowman""s capsule, the renal tubular epithelium, inflamed tissue during heart and kidney transplant rejection and by intestinal tissue in graft-versus-host disease. VCAM-1 is also found to be expressed on those tissue areas of the arterial endothelium which correspond to early arteriosclerotic plaques of a rabbit model. Additionally, VCAM-1 is expressed on follicular dendritic cells of human lymph nodes and is found on stroma cells of the bone marrow, for example in the mouse. The latter finding points to a function of VCAM-1 in B-cell development. Apart from on cells of hematopoietic origin, VLA-4 is also found, for example, on melanoma cell lines, and the VCAM-1/VLA-4 adhesion mechanism is connected with the metastasis of such tumors (Rice et al., Science 1989,246, 1303).
The main form in which VCAM-1 occurs in vivo on endothelial cells and which is the dominant form in vivo is designated as VCAM-7D and carries seven immunoglobulin domains. The domains 4, 5 and 6 are similar in their amino acid sequences to the domains 1, 2 and 3. In a further form consisting of six domains, designated here as VCAM-6D, the fourth domain is removed by alternative splicing. VCAM-6D can also bind VLA-4-expressing cells.
Further details on VLA-4, VCAM-1, integrins and adhesion proteins are found, for example, in the articles by Kilger and Holzmann, J. Mol. Meth. 1995, 73, 347; Elices, Cell Adhesion in Human Disease, Wiley, Chichester 1995, p. 79; Kuijpers, Springer Semin. Immunopathol. 1995,16, 379.
On account of the role of the VCAM-1/VLA-4 mechanism in cell adhesion processes, which are of importance, for example, in infections, inflammations or atherosclerosis, it has been attempted by means of interventions into these adhesion processes to control illnesses, in particular, for example, inflammations (Osborn et al., Cell 1989, 59, 1203). A method of doing this is the use of monoclonal antibodies which are directed against VLA-4. Monoclonal antibodies (mABs) of this type, which as VLA-4 antagonists block the interaction between VCAM-1 and VLA-4, are known. Thus, for example, the anti-VLA-4 mABs HP2/1 and HP1/3 inhibit the adhesion of VLA-4-expressing Ramos cells (B-cell-like cells) to human umbilical cord endothelial cells and to VCAM-1-transfected COS cells. The anti-VCAM-1 mAB 4B9 likewise inhibits the adhesion of Ramos cells, Jurkat cells (T-cell-like cells) and HL60 cells (granulocyte-like cells) to COS cells transfected with genetic constructs which cause VCAM-6D and VCAM-7D to be expressed. In vitro data with antibodies which are directed against the xcex14 subunit of VLA-4 show that the adhesion of lymphocytes to synovial endothelial cells is blocked, an adhesion which plays a part in rheumatoid arthritis (van Dinther-Janssen et al., J. Immunol. 1991,147, 4207).
In vivo experiments have shown that an experimental autoimmune encephalomyelitis can be inhibited by anti-xcex14 mAB. The migration of leukocytes into an inflammatory focus is likewise blocked by a monoclonal antibody against the xcex14 chain of VLA-4. The influencing of the VLA-4-dependent adhesion mechanism by antibodies was also investigated in an asthma model in order to investigate the role of VLA-4 in the recruitment of leukocytes into inflamed lung tissue (WO-A-93/13798). The administration of anti-VLA-4 antibodies inhibited the late-phase reaction and airway overreaction in allergic sheep.
The VLA-4-dependent cell adhesion mechanism was also investigated in a primate model of inflammatory bowel disease (IBD). In this model, which corresponds to ulcerative colitis in man, the administration of anti-VLA-4 antibodies resulted in a significant reduction in the acute inflammation.
Moreover, it was possible to show that VLA-4-dependent cell adhesion plays a part in the following clinical conditions including the following chronic inflammatory processes: rheumatoid arthritis (Cronstein and Weismann, Arthritis Rheum. 1993, 36, 147; Elices et al., J. Clin. Invest. 1994, 93, 405), diabetes mellitus (Yang et al., Proc. Natl. Acad. Sci. USA 1993, 90, 10494), systemic lupus erythematosus (Takeuchi et al., J. Clin. Invest. 1993, 92, 3008), allergies of the delayed type (type IV allergy) (Elices et al., Clin. Exp. Rheumatol. 1993, 11, S77), multiple sclerosis (Yednock et al., Nature 1992, 356, 63), malaria (Ockenhouse et al., J. Exp. Med. 1992, 176, 1183), arteriosclerosis (O""Brien et al., J. Clin. Invest. 1993, 92, 945), transplantation (Isobe et al., Transplantation Proceedings 1994, 26, 867), various malignancies, for example melanoma (Renkonen et al., Am. J. Pathol. 1992,140, 763), lymphoma (Freedman et al., Blood 1992, 79, 206) and others (Albelda et al., J. Cell Biol. 1991, 114,1059).
VLA-4 blocking by suitable antagonists accordingly offers effective therapeutic possibilities, in particular, for example, of treating various inflammatory conditions including asthma and IBD. The particular relevance of VLA-4 antagonists for the treatment of rheumatoid arthritis in this case results, as already stated, from the fact that leukocytes from the blood must first adhere to endothelial cells before they can migrate into the synovium, and that the VLA-4 receptor plays a part in this adhesion. The fact that VCAM-1 is induced by inflammatory agents on endothelial cells (Osborn, Cell 1990, 62, 3; Stoolman, Cell 1989, 56, 907), and the recruitment of various leukocytes into areas of infection and inflammatory foci has already been discussed above. At the same time, T cells adhere to activated endothelium mainly via the LFA-1/ICAM-1 and VLA-4/VCAM-1 adhesion mechanisms (Springer, Cell 1994, 76, 301). On most synovial T cells, the binding capacity of VLA-4 for VCAM-1 is increased in rheumatoid arthritis (Postigo et al., J. Clin. Invest. 1992, 89, 1445). Additionally, an increased adhesion of synovial T cells to fibronectin has been observed (Laffon et al., J. Clin. Invest. 1991, 88, 546; Morales-Ducret et al., J. Immunol. 1992,149, 1424). VLA-4 is upregulated both in the course of its expression and with respect to its function on T lymphocytes of the rheumatoid synovial membrane. The blocking of the binding of VLA-4 to its physiological ligands VCAM-1 and fibronectin makes possible an effective prevention or alleviation of articular inflammatory processes. This is also confirmed by experiments with the antibody HP2/1 on Lewis rats with adjuvant arthritis, in which an effective prevention of illness has been observed (Barbadillo et al., Springer Semin. Immunopathol. 1995, 16, 427). VLA-4 is thus an important therapeutic target molecule.
The abovementioned VLA-4 antibodies and the use of antibodies as VLA-4 antagonists are described in the Patent Applications WO-A-93/13798, WO-A-93/15764, WO-A-94/16094, WO-A-94/17828 and WO-A-95/19790. In the Patent Applications WO-A-94/15958, WO-A-95/15973, WO-A-96/00581, WO-A-96/06108 and WO-A-96/20216, peptide compounds are described as VLA-4 antagonists. The use of antibodies and peptide compounds as pharmaceuticals, however, has some disadvantages, for example lack of oral availability, easy degradability or immunogenic action on longer-term use, and there is thus a need for VLA-4 antagonists having a favorable profile of properties for use in therapy and prophylaxis.
WO-A-95/14008, WO-A-93/18057, U.S. Pat. Nos. 5,658,935, 5,686,421, 5,389,614, 5,397,796, 5,424,293 and 5,554,594, which are herein incorporated by reference, describe substituted 5-membered ring heterocycles which have an amino, amidino or guanidino function at the N-terminal end of the molecule and which exhibit platelet aggregation-inhibiting actions. EP-A-796 855 describes further heterocycles which are inhibitors of bone resorption. EP-A-842 943, EP-A-842 945 and EP-A-842 944 describe that compounds from this series and further compounds surprisingly also inhibit leukocyte adhesion and are VLA-4 antagonists.
EP-A-903 353, EP-A-905 139 and EP-A-918 059 and WO-A-99/60015 (German patent application 19821483.9) describe further compounds which inhibit leukocyte adhesion and are VLA-4 antagonists. The properties of these compounds, however, are still not satisfactory in various respects and there is a need for compounds having a further improved property profile. EP-A-91 8 059 describes, inter alia, imidazolidine derivatives which contain a spiro-linked ring system on the imidazolidine ring. Not specifically disclosed, however, are the spiroimidazolidine derivatives of the present invention, which are distinguished by their advantageous property profile.
The present invention relates to a compound, and physiologically acceptable salts thereof, in all its stereoisomeric forms and mixtures thereof in all ratios, of the formula I: 
where R1 is hydrogen or methyl; where R2 is phenyl or (C1-C4)-alkyl; where X is xe2x80x94CH2xe2x80x94CH2xe2x80x94 or xe2x80x94CH2xe2x80x94CH2xe2x80x94CH2xe2x80x94, where one of the CH2 groups in these two residues can be replaced by a carbonyl group Cxe2x95x90O; where W is isopropyl or cyclopropyl; where V is hydrogen or methoxy; where E is xe2x80x94COxe2x80x94R3, xe2x80x94COxe2x80x94H, xe2x80x94CH2xe2x80x94Oxe2x80x94R4, xe2x80x94CH2xe2x80x94Oxe2x80x94COxe2x80x94R4, xe2x80x94CH2xe2x80x94Oxe2x80x94COxe2x80x94Oxe2x80x94R5 or 5-tetrazolyl; where R3 is hydroxy, (C1-C10)-alkoxy, phenyl-(C1-C8)-alkoxy-, phenyloxy-, (C1-C8)-alkylcarbonyloxy-(C1-C6)-alkoxy-, phenylcarbonyloxy-(C1-C6)-alkoxy-, phenyl-(C1-C6)-alkylcarbonyloxy-(C1-C6)-alkoxy-, (C1-C8)-alkoxycarbonyloxy-(C1-C6)-alkoxy-, phenyloxycarbonyloxy-(C1-C6)-alkoxy-, phenyl-(C1-C6)-alkoxycarbonyloxy-(C1-C6)-alkoxy-, amino, mono-((C1-C10)-alkyl)-amino-, di-((C1-C10)-alkyl)-amino- or R4R4Nxe2x80x94COxe2x80x94(C1-C6)-alkoxy- in which the residues R4 are independent of one another and can be identical or different; where R4 is hydrogen, (C1-C10)-alkyl, phenyl or phenyl-(C1-C8)-alkyl-; where R5 has one of the meanings of R4 with the proviso that R4 is not hydrogen; where phenyl is an unsubstituted phenyl residue or a phenyl residue which is substituted by one or more identical or different substituents from the group consisting of (C1-C4)-alkyl, (C1-C4)-alkoxy, methylenedioxy, ethylenedioxy, halogen, trifluoromethyl and trifluoromethoxy.
In one embodiment, the invention relates to a compound of the formula where W is isopropyl and V is hydrogen. In another embodiment, the invention relates to a compound of the formula I where R2 is unsubstituted phenyl, phenyl substituted by a methylenedioxy residue or an ethylenedioxy residue, or phenyl substituted by one or two (C1-C4)-alkoxy groups, or (C1-C4)-alkyl. In yet another embodiment, the invention relates to a compound of the formula I where E is xe2x80x94COxe2x80x94R3 or xe2x80x94CH2xe2x80x94OH and R3 is hydroxy, a (C1-C6)-alkoxy or an amino group.
In yet another embodiment, the invention relates to a compound of the formula I where R1 is hydrogen or methyl, where R2 is unsubstituted phenyl, phenyl substituted by a methylenedioxy residue or an ethylenedioxy residue, phenyl substituted by one or two methoxy groups, or (C1-C4)-alkyl; where X is xe2x80x94CH2xe2x80x94CH2xe2x80x94 or xe2x80x94CH2xe2x80x94CH2xe2x80x94CH2xe2x80x94, where one of the CH2 groups in these two residues can be replaced by a carbonyl group Cxe2x95x90O; where W is isopropyl or cyclopropyl; where V is hydrogen or methoxy; and where E is xe2x80x94COxe2x80x94OH, xe2x80x94COxe2x80x94Oxe2x80x94(C1-C4)-alkyl, xe2x80x94COxe2x80x94NH2 or xe2x80x94CH2xe2x80x94OH.
The invention also relates to a process for the preparation of a compound of the formula I which includes performing a condensation of a compound of the formula II with a compound of the formula III 
where, in the formulae II and III, the groups E, V, W, X, R1 and R2 are defined as set forth above with reference to formula I or alternatively functional groups are present in protected form or in the form of a precursor, and where G is hydroxycarbonyl, (C1-C6)-alkoxycarbonyl or an activated carboxylic acid derivative.
In another embodiment, the invention relates to prodrugs of a compound of the formula I for use as pharmaceuticals. In yet another embodiment, the invention relates to a pharmaceutical preparation, which includes one or more compounds of the formula I together with a pharmaceutically acceptable carrier. In a preferred embodiment, the pharmaceutical preparation may be used as an antiinflammatory, for the therapy or prophylaxis of, for example, arthritis, rheumatoid arthritis, polyarthritis, inflammatory bowel disease, systemic lupus erythematosus, multiple sclerosis, inflammatory disorders of the central nervous system, asthma, allergies, cardiovascular disorders, arteriosclerosis, restenoses, diabetes, damage to organ transplants, immune disorders, autoimmune disorders, tumor growth or tumor metastasis, or malaria. In yet another embodiment, the invention relates to a pharmaceutical preparation, which includes one or more compounds of the formula I together with a pharmaceutically acceptable carrier which may be used as an inhibitor of the adhesion and/or migration of leukocytes or for the inhibition of the VLA-4 receptor.
The above and other advantages and features of the invention will be more clearly understood from the following detailed description
In the following detailed description, reference is made to specific embodiments by which the invention may be practiced. These embodiments are described in sufficient detail to enable those skilled in the art to practice the invention, and it is to be understood that other embodiments may be utilized, and that changes may be made without departing from the spirit and scope of the present invention.
The present invention relates to compounds of the formula I 
in which
R1 is hydrogen or methyl;
R2 is phenyl or (C1-C4)-alkyl;
X is xe2x80x94CH2xe2x80x94CH2xe2x80x94 or xe2x80x94CH2xe2x80x94CH2xe2x80x94CH2xe2x80x94, where one of the CH2 groups in these two residues can be replaced by a carbonyl group Cxe2x95x90O;
W is isopropyl or cyclopropyl;
V is hydrogen or methoxy;
E is xe2x80x94COxe2x80x94R3, xe2x80x94COxe2x80x94H, xe2x80x94CH2xe2x80x94Oxe2x80x94R4, xe2x80x94CH2xe2x80x94Oxe2x80x94COxe2x80x94R4, xe2x80x94CH2xe2x80x94Oxe2x80x94COxe2x80x94Oxe2x80x94R5 or 5-tetrazolyl;
R3 is hydroxy, (C1-C10)-alkoxy, phenyl-(C1-C8)-alkoxy-, phenyloxy-, (C1-C8)-alkylcarbonyloxy-(C1-C6)-alkoxy-, phenylcarbonyloxy-(C1-C6)-alkoxy-, phenyl-(C1-C6)-alkylcarbonyloxy-(C1-C6)-alkoxy-, (C1-C8)-alkoxycarbonyloxy-(C1-C6)-alkoxy-, phenyloxycarbonyloxy-(C1-C6)-alkoxy-, phenyl-(C1-C6)-alkoxycarbonyloxy-(C1-C6)-alkoxy-, amino, mono-((C1-C10)-alkyl)-amino-, di-((C1-C10)-alkyl)-amino- or R4R4Nxe2x80x94COxe2x80x94(C1-C6)-alkoxy- in which the residues R4 are independent of one another and can be identical or different;
R4 is hydrogen, (C1-C10)-alkyl, phenyl or phenyl-(C1-C8)-alkyl-;
R5 has one of the meanings of R4 with the exception of hydrogen;
phenyl is an unsubstituted phenyl residue or a phenyl residue which is substituted by one or more identical or different substituents from the group consisting of (C1-C4)-alkyl, (C1-C4)-alkoxy, methylenedioxy, ethylenedioxy, halogen, trifluoromethyl and trifluoromethoxy;
in all their stereoisomeric forms and mixtures thereof in all ratios,
and their physiologically acceptable salts.
If a residue occurs more than once in a compound of the formula I for example if R2 is phenyl and a further phenyl residue is contained in the group E, the residues are in all cases independent of one another and can be identical or different.
Alkyl residues can be straight-chain or branched. This also applies if they carry substituents or occur as substituents of other residues, for example in alkoxy residues, alkoxycarbonyl residues or arylalkyl residues. Examples of suitable alkyl residues are methyl, ethyl, n-propyl, n-butyl, n-pentyl, n-hexyl, n-heptyl, n-octyl, n-nonyl, n-decyl, isopropyl, isobutyl, isopentyl, isohexyl, 3-methylpentyl, neopentyl, neohexyl, 2,3,5-trimethylhexyl, sec-butyl, tert-butyl, tert-pentyl. Preferred alkyl residues are methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, n-hexyl and isohexyl. Substituted alkyl residues can be substituted in any desired positions.
If the divalent residue X in the formula I is the divalent 1,2-ethylene residue xe2x80x94CH2xe2x80x94CH2xe2x80x94, that is if X together with the two CH2 groups to which X is bonded forms a tetramethylene residue, the compounds of the formula I contain a spiro-linked cyclopentane ring, and thus compounds of the formula Ia are present which can be designated as 4,4-tetramethyleneimidazolidine derivatives. 
If, in the compounds of the formula Ia, one of the CH2 groups in the cyclopentane ring is replaced by a Cxe2x95x90O group, that is if X in the formula I is the group xe2x80x94CH2xe2x80x94COxe2x80x94 or xe2x80x94COxe2x80x94CH2xe2x80x94, compounds of the formula Ib are present. 
In the compounds of the formula Ib, X together with the two CH2 groups in the formula I to which X is bonded forms a 2-oxotetramethylene residue xe2x80x94CH2xe2x80x94COxe2x80x94CH2xe2x80x94CH2xe2x80x94. The compounds of the formula Ib can be designated as 4,4-(2-oxotetramethylene)imidazolidine derivatives.
If the divalent residue X in the formula I is the divalent 1,3-propylene residue xe2x80x94CH2xe2x80x94CH2xe2x80x94CH2xe2x80x94, that is if X together with the two CH2 groups to which X is bonded forms a pentamethylene residue, the compounds of the formula I contain a spiro-linked cyclohexane ring, and thus compounds of the formula Ic are present which can be designated as 4,4-pentamethyleneimidazolidine derivatives. 
If, in the compounds of the formula Id, one of the CH2 groups in the cyclohexane ring is replaced by a Cxe2x95x90O group, that is if X is one of the groups xe2x80x94COxe2x80x94CH2xe2x80x94CH2xe2x80x94, xe2x80x94CH2xe2x80x94COxe2x80x94CH2xe2x80x94 or xe2x80x94CH2xe2x80x94CH2xe2x80x94COxe2x80x94, compounds of the formulae Id or Ie are present. 
In the compounds of the formulae Id and Ie, X together with the two CH2 groups in the formula I to which X is bonded forms a 2-oxopentamethylene residue xe2x80x94CH2xe2x80x94COxe2x80x94CH2xe2x80x94CH2xe2x80x94CH2xe2x80x94 or a 3-oxopentamethylene residue xe2x80x94CH2xe2x80x94CH2xe2x80x94COxe2x80x94CH2xe2x80x94CH2xe2x80x94. The compounds of the formulae Id and Ie can be designated as 4,4-(2-oxopentamethylene)imidazolidine derivatives and 4,4-(3-oxopentamethylene)-imidazolidine derivatives. If, in the residue xe2x80x94CH2xe2x80x94CH2xe2x80x94CH2xe2x80x94 representing X, a CH2 group is replaced by a carbonyl group, the middle CH2 group is preferably replaced, that is preferably compounds of the formula Ie are present in this case.
Phenyl residues are unsubstituted or are monosubstituted or polysubstituted, for example monosubstituted, disubstituted, trisubstituted, tetrasubstituted or pentasubstituted, by identical or different residues. If a phenyl residue is substituted, it preferably carries one or two identical or different substituents. The same applies, for example, to substituted phenyl residues in groups such as phenylalkyl, phenylcarbonyl, etc. Phenylalkyl residues are, for example, benzyl, 1-phenylethyl or 2-phenylethyl, preferably benzyl, all of which can also be substituted.
In monosubstituted phenyl residues, the substituent can be located in the 2-position, the 3-position or the 4-position. In disubstituted phenyl residues, the substituents can be located in the 2,3-position, 2,4-position, 2,5-position, 2,6-position, 3,4-position or 3,5-position. In trisubstituted phenyl residues, the substituents can be located in the 2,3,4-position, 2,3,5-position, 2,4,5-position, 2,4,6-position, 2,3,6-position or 3,4,5-position. If a phenyl residue carries substituents from the group consisting of methylenedioxy (xe2x80x94Oxe2x80x94CH2xe2x80x94Oxe2x80x94) and ethylenedioxy (xe2x80x94Oxe2x80x94CH2xe2x80x94CH2xe2x80x94Oxe2x80x94), it preferably carries only one substituent from this group (optionally in addition to other substituents).
Examples of substituted phenyl residues which, for example, can be R2, are 2-methylphenyl, 3-methylphenyl, 4-methylphenyl, 2,3-dimethylphenyl, 2,4-dimethylphenyl, 2,5-dimethylphenyl, 2,6-dimethylphenyl, 3,4-dimethylphenyl, 3,5-dimethylphenyl, 2,4,5-trimethylphenyl, 2,4,6-trimethylphenyl, 3,4,5-trimethylphenyl, 2-(n-butyl)phenyl, 3-(n-butyl)phenyl, 4-(n-butyl)phenyl, 2-isobutylphenyl, 3-isobutylphenyl, 4-isobutylphenyl, 3-tert-butylphenyl, 4-tert-butylphenyl, 2-methoxyphenyl, 3-methoxyphenyl, 4-methoxyphenyl, 2,3-dimethoxyphenyl, 2,4-dimethoxyphenyl, 2,5-dimethoxyphenyl, 2,6-dimethoxyphenyl, 3,4-dimethoxyphenyl, 3,5-dimethoxyphenyl, 2,4,5-trimethoxyphenyl, 2,4,6-trimethoxyphenyl, 3,4,5-trimethoxyphenyl, 2-(n-butoxy)phenyl, 3-(n-butoxy)phenyl, 4-(n-butoxy)phenyl, 2-isobutoxyphenyl, 3-isobutoxyphenyl, 4-isobutoxyphenyl, 2-tert-butoxyphenyl, 3-tert-butoxyphenyl, 4-tert-butoxyphenyl, 2,3-methylenedioxyphenyl, 3,4-methylenedioxyphenyl, 2,3-ethylenedioxyphenyl, 3,4-ethylenedioxyphenyl, 2-fluorophenyl, 3-fluorophenyl, 4-fluorophenyl, 2,3-difluorophenyl, 2,4-difluorophenyl, 2,5-difluorophenyl, 2,6-difluorophenyl, 3,4-difluorophenyl, 3,5-difluorophenyl, 2,4,5-trifluorophenyl, 2,4,6-trifluorophenyl, 3,4,5-trifluorophenyl, 2,3,5,6-tetrafluorophenyl, 2,3,4,5,6-pentafluorophenyl, 2-chlorophenyl, 3-chlorophenyl, 4-chlorophenyl, 2,3-dichlorophenyl, 2,4-dichlorophenyl, 2,5-dichlorophenyl, 2,6-dichlorophenyl, 3,4-dichlorophenyl, 3,5-dichlorophenyl, 2-bromophenyl, 3-bromophenyl, 4-bromophenyl, 3-iodophenyl, 4-iodophenyl, 2-trifluoromethylphenyl, 3-trifluoromethylphenyl, 4-trifluoromethylphenyl, 3,4-bis(trifluoromethyl)phenyl, 3,5-bis(trifluoromethyl)phenyl, 2-trifluoromethoxyphenyl, 3-trifluoromethoxyphenyl, 4-trifluoromethoxyphenyl, etc. In substituted phenyl residues, however, different substituents can also be contained in any desired combination, such as, for example, in the residues 3-methoxy-4-methylphenyl, 4-fluoro-3-methoxyphenyl, 3-fluoro-4-methoxyphenyl, 3,5-difluoro-4-methoxyphenyl, 3-fluoro-4,5-methylenedioxyphenyl, 3-fluoro-4,5-ethylenedioxyphenyl, 2-chloro-3-methylphenyl, 3-chloro-4-methylphenyl, 3-chloro-4-fluorophenyl, etc.
Halogen may be fluorine, chlorine, bromine or iodine, preferably fluorine or chlorine.
Physiologically acceptable salts of the compounds of the formula I are preferably nontoxic or pharmaceutically utilizable salts. Salts of this type of compounds of the formula I which contain acidic groups, for example a carboxylic acid group representing the group E, are, for example, alkali metal salts or alkaline earth metal salts such as, for example, sodium salts, potassium salts, magnesium salts and calcium salts, or ammonium salts such as, for example, salts with physiologically acceptable quaternary ammonium ions and acid addition salts with ammonia and physiologically acceptable organic amines, such as, for example, methylamine, ethylamine, triethylamine, 2-hydroxyethylamine, tris(2-hydroxyethyl)amine, xcex1,xcex1,xcex1-tris(hydroxymethyl)methylamine (tromethamine) or amino acids, preferably basic amino acids. Salts of an acidic compound of the formula I and an organic amine can contain the two components in the ratio 1:1 (or about 1:1) or in another ratio, for example in a ratio of about 1:0.5 to about 1:4 (1 molecule of the formula I to 0.5 to 4 molecules of the amine), preferably in a ratio of about 1:0.5 to about 1:2 (1 molecule of the formula I to 0.5 to 2 molecules of the amine).
Compounds of the formula I which contain basic groups, for example an amino group in the alcohol component of a carboxylic acid ester group, form salts with inorganic acids such as, for example, hydrochloric acid, sulfuric acid or phosphoric acid, and with organic carboxylic acids or sulfonic acids such as, for example, acetic acid, citric acid, benzoic acid, maleic acid, fumaric acid, tartaric acid, methanesulfonic acid or p-toluenesulfonic acid. Compounds which contain both acidic groups and basic groups can also be present in the form of inner salts or betaines or zwitterions, which are likewise included by the present invention.
Salts can be obtained from the compounds of the formula I according to customary processes known to the person skilled in the art, for example by combination with an organic or inorganic acid or base in a solvent or diluent, or also from other salts by anion exchange or cation exchange.
The compounds of the formula I can be present in stereoisomeric forms. On all asymmetric centers in the compounds of the formula I, independently of one another the S configuration or the R configuration can be present or a R/S mixture can be present. Thus the asymmetric carbon atom to which the residue R2 is bonded can have the R configuration or S configuration or the compound of the formula I can be present, with respect to this carbon atom, as an R/S mixture. Likewise, the asymmetric carbon atom to which the group xe2x80x94CH2xe2x80x94W, which is an isobutyl group (=2-methylpropyl group) or a cyclopropylmethyl group, and the imidazolidine ring are bonded can have the R configuration or S configuration or the compound of the formula I can be present with respect to this carbon atom as an R/S mixture. All other asymmetric carbon atoms can also have the R configuration or the S configuration or the compound of the formula I can be present with respect to each of these carbon atoms as an R/S mixture.
The invention includes all possible stereoisomers of the compounds of the formula I, for example pure or largely pure enantiomers and pure or largely pure diastereomers and mixtures of two or more stereoisomeric forms, for example mixtures of enantiomers and/or diastereomers, in all ratios. Enantiomers are thus a subject of the invention in enantiomerically pure form, both as levorotatory and as dextrorotatory antipodes, in the form of racemates and in the form of mixtures of the two enantiomers in all ratios. Likewise, diastereomers in diastereomerically pure form and in the form of mixtures in all ratios are a subject of the invention. Examples of individual stereoisomers which are a subject of the invention are the compounds of the formulae If, Ig, Ih and Ii. 
The individual stereoisomers can be prepared, if desired, by use of stereochemically uniform starting substances in the synthesis, by stereoselective synthesis or by separation of a mixture according to customary methods, for example by chromatography or crystallization, in the case of enantiomers for example by chromatography on chiral phases. Optionally, before separation of stereoisomers a derivatization can be carried out. The separation of a stereoisomer mixture can take place at the stage of the compounds of the formula I or at the stage of a starting substance or of an intermediate in the course of the synthesis.
The compounds of the formula I according to the invention can contain mobile hydrogen atoms, that is be present in various tautomeric forms. All tautomers of the compounds of the formula I are also a subject of the present invention. The present invention also includes solvates and addition compounds or adducts of compounds of the formula I, for example adducts with water, that is hydrates, or adducts with alcohols or amines. The invention furthermore includes derivatives of compounds of the formula I, for example esters, amides, prodrugs and other physiologically acceptable derivatives, and also active metabolites of compounds of the formula I. The invention also relates to prodrugs of the compounds of the formula I, which can be converted into compounds of the formula I under physiological conditions. Suitable prodrugs of the compounds of the formula I, that is chemically modified derivatives of the compounds of the formula I having desirably improved properties, are known to the person skilled in the art. Details of prodrugs are found, for example, in Fleisher et al., Advanced Drug Delivery Reviews 19 (1996) 115; Design of Prodrugs, H. Bundgaard, Ed., Elsevier, 1985; H. Bundgaard, Drugs of the Future 16 (1991) 443. Possible prodrugs of the compounds of the formula I are especially ester prodrugs, amide prodrugs, aldehyde prodrugs and alcohol prodrugs of carboxylic acid groups. Examples of ester prodrugs and amide prodrugs which may be mentioned are (C1-C4)-alkyl esters such as methyl esters, ethyl esters, isopropyl esters, isobutyl esters, substituted alkyl esters such as hydroxyalkyl esters, acyloxyalkyl esters, aminoalkyl esters, acylaminoalkyl esters, dialkylaminoalkyl esters, unsubstituted amides or Nxe2x80x94(C1-C4)-alkylamides such as methylamides or ethylamides.
With respect to the structural elements V and W, the present invention includes four embodiments each of which expressly is a subject of the present invention. In one of these embodiments, the group W in the formula I is isopropyl, that is the residue xe2x80x94CH(CH3)2, and at the same time V is hydrogen. This embodiment thus includes compounds of the formula Ik 
in which
R1 is hydrogen or methyl;
R2 is phenyl or (C1-C4)-alkyl;
X is xe2x80x94CH2xe2x80x94CH2xe2x80x94 or xe2x80x94CH2xe2x80x94CH2xe2x80x94CH2xe2x80x94, where one of the CH2 groups in these two residues can be replaced by a carbonyl group Cxe2x95x90O;
E is xe2x80x94COxe2x80x94R3, xe2x80x94COxe2x80x94H, xe2x80x94CH2xe2x80x94Oxe2x80x94R4, xe2x80x94CH2xe2x80x94Oxe2x80x94COxe2x80x94R4, xe2x80x94CH2xe2x80x94Oxe2x80x94COxe2x80x94Oxe2x80x94R5 or 5-tetrazolyl;
R3 is hydroxy, (C1-C10)-alkoxy, phenyl-(C1-C8)-alkoxy-, phenyloxy-, (C1-C8)-alkylcarbonyloxy-(C1-C6)-alkoxy-, phenylcarbonyloxy-(C1-C6)-alkoxy-, phenyl-(C1-C6)-alkylcarbonyloxy-(C1-C6)-alkoxy-, (C1-C8)-alkoxycarbonyloxy-(C1-C6)-alkoxy-, phenyloxycarbonyloxy-(C1-C6)-alkoxy-, phenyl-(C1-C6)-alkoxycarbonyloxy-(C1-C6)-alkoxy-, amino, mono-((C1-C10)-alkyl)-amino-, di-((C1-C10)-alkyl)-amino- or R4R4Nxe2x80x94COxe2x80x94(C1-C6)-alkoxy- in which the residues R4 are independent of one another and can be identical or different;
R4 is hydrogen, (C1-C10)-alkyl, phenyl or phenyl-(C1-C8)-alkyl-;
R5 has one of the meanings of R4 with the exception of hydrogen;
phenyl is an unsubstituted phenyl residue or a phenyl residue which is substituted by one or more identical or different substituents from the group consisting of (C1-C4)-alkyl, (C1-C4)-alkoxy, methylenedioxy, ethylenedioxy, halogen, trifluoromethyl and trifluoromethoxy;
in all their stereoisomeric forms and mixtures thereof in all ratios,
and their physiologically acceptable salts.
A second of these four embodiments relates to compounds of the formula I in which W is cyclopropyl, that is the residue 
and at the same time V is hydrogen. A third embodiment relates to compounds of the formula I in which W is isopropyl and at the same time V is methoxy, that is the residue xe2x80x94OCH3. A fourth embodiment relates to compounds of the formula I in which W is cyclopropyl and at the same time V is methoxy. A subgroup of the compounds according to the invention includes the compounds of the second, third and fourth embodiment described above, that is compounds of the formula I in which V is hydrogen or methoxy and W is isopropyl or cyclopropyl, but in which not at the same time V is hydrogen and W is isopropyl. Also the compounds of the second, third and fourth embodiment of the invention are a subject of the invention in all their stereoisomeric forms and mixtures thereof in all ratios and in the form of their physiologically acceptable salts.
The individual structural elements in the formula I preferably have the following meanings, which they can have independently of one another.
E is preferably xe2x80x94COxe2x80x94R3, xe2x80x94COxe2x80x94H, xe2x80x94CH2xe2x80x94Oxe2x80x94R4, xe2x80x94CH2xe2x80x94Oxe2x80x94COxe2x80x94R4 or xe2x80x94CH2xe2x80x94Oxe2x80x94COxe2x80x94OR5, particularly preferably xe2x80x94COxe2x80x94R3, xe2x80x94COxe2x80x94H, xe2x80x94CH2xe2x80x94Oxe2x80x94R4 or xe2x80x94CH2xe2x80x94Oxe2x80x94COxe2x80x94R4, very particularly preferably xe2x80x94COxe2x80x94R3, xe2x80x94CH2xe2x80x94Oxe2x80x94R4 or xe2x80x94CH2xe2x80x94Oxe2x80x94COxe2x80x94R4, moreover preferably xe2x80x94COxe2x80x94R3 or xe2x80x94CH2xe2x80x94Oxe2x80x94R4, especially preferably xe2x80x94COxe2x80x94R3. A residue xe2x80x94CH2xe2x80x94Oxe2x80x94R4 representing the group E is preferably the hydroxymethyl residue xe2x80x94CH2xe2x80x94OH. Especially preferred meanings of E are xe2x80x94COxe2x80x94Oxe2x80x94(C1-C4)-alkyl, xe2x80x94COxe2x80x94OH, xe2x80x94COxe2x80x94NH2 and xe2x80x94CH2xe2x80x94OH, preferably xe2x80x94COxe2x80x94OH, xe2x80x94COxe2x80x94NH2 and xe2x80x94CH2xe2x80x94OH, most preferably xe2x80x94COxe2x80x94OH.
X is preferably xe2x80x94CH2xe2x80x94CH2xe2x80x94 or xe2x80x94CH2xe2x80x94CH2xe2x80x94CH2xe2x80x94, more preferably xe2x80x94CH2xe2x80x94CH2xe2x80x94CH2xe2x80x94, where none of the CH2 groups is replaced by a carbonyl group.
R2 is preferably unsubstituted phenyl, phenyl which is substituted by a methylenedioxy residue or an ethylenedioxy residue, phenyl which is substituted by one or two (C1-C4)-alkoxy groups, preferably by methoxy groups, or (C1-C4)-alkyl, where the (C1-C4)-alkyl group preferably is methyl, ethyl or isobutyl, more preferably methyl or ethyl, particularly preferably methyl. Particularly preferably, R2 is unsubstituted phenyl, phenyl which is substituted by a methylenedioxy residue or an ethylenedioxy residue, phenyl which is substituted by one or two methoxy groups, or methyl. Very particularly preferably, R2 is unsubstituted phenyl, 3,4-methylene-dioxyphenyl, 3,4-ethylenedioxyphenyl, 2-methoxyphenyl, 3-methoxyphenyl, 4-methoxyphenyl, 2,3-dimethoxyphenyl, 2,4-dimethoxyphenyl, 2,5-dimethoxyphenyl, 2,6-dimethoxyphenyl, 3,4-dimethoxyphenyl, 3,5-dimethoxyphenyl or methyl.
R3 is preferably hydroxy, (C1-C6)-alkoxy or amino (xe2x80x94NH2), particularly preferably hydroxy, (C1-C4)-alkoxy or amino, very particularly preferably hydroxy or amino, especially preferably hydroxy.
R4 is preferably hydrogen or (C1-C6)-alkyl, particularly preferably hydrogen or (C1-C4)-alkyl. R5 is preferably (C1-C6)-alkyl, particularly preferably (C1-C4)-alkyl.
Preferred compounds of the formula I are those which have a uniform configuration on one or on more chiral centers, for example on the carbon atom which carries the residue R2, and/or on the carbon atom which carries the group xe2x80x94CH2xe2x80x94W. That is, compounds are preferred which are present in uniform or in essentially uniform configuration on one or more chiral centers, either in the R configuration or in the S configuration, but not as an R/S mixture. As explained, the individual chiral centers in these compounds of the formula I, however, can independently of one another have the R configuration or the S configuration and can have identical or different configurations. Particularly preferred compounds of the formula I are those in which the carbon atom which carries the group xe2x80x94CH2xe2x80x94W is present in the S configuration, that is in the configuration with respect to this stereocenter which is shown in the formulae If and Ig. Particularly preferred compounds of the formula I are also those in which the carbon atom which carries the group R2 is present in the configuration shown in the formulae If and Ih. If R2 is phenyl or substituted phenyl, in these particularly preferred compounds the carbon atom which carries the group R2 has the S configuration, if R2 is, for example, methyl, ethyl or isobutyl, it has the R configuration. Very particularly preferred compounds of the formula I are those in which the two abovementioned stereocenters are present in the configurations shown in the formula If.
Preferred compounds of the formula I are those compounds in which one or more of the residues have preferred meanings or have a specific meaning from the listed meanings, all combinations of preferred meanings of residues being a subject of the present invention.
Particularly preferred compounds include compounds of the formula I, in which
R1 is hydrogen or methyl;
R2 is unsubstituted phenyl, phenyl which is substituted by a methylenedioxy residue or an ethylenedioxy residue, phenyl which is substituted by one or two (C1-C4)-alkoxy groups, or (C1-C4)-alkyl;
X is xe2x80x94CH2xe2x80x94CH2xe2x80x94 or xe2x80x94CH2xe2x80x94CH2xe2x80x94CH2xe2x80x94, where one of the CH2 groups in these two residues can be replaced by a carbonyl group Cxe2x95x90O;
W is isopropyl or cyclopropyl;
V is hydrogen or methoxy;
E is xe2x80x94COxe2x80x94R3, xe2x80x94COxe2x80x94H, xe2x80x94CH2xe2x80x94Oxe2x80x94R4, xe2x80x94CH2xe2x80x94Oxe2x80x94COxe2x80x94R4 or xe2x80x94CH2xe2x80x94Oxe2x80x94COxe2x80x94Oxe2x80x94R5;
R3 is hydroxy, (C1-C10)-alkoxy, phenyl-(C1-C8)-alkoxy-, phenyloxy-, (C1-C8)-alkylcarbonyloxy-(C1-C6)-alkoxy-, phenylcarbonyloxy-(C1-C6)-alkoxy-, phenyl-(C1-C6)-alkylcarbonyloxy-(C1-C6)-alkoxy-, (C1-C8)-alkoxycarbonyloxy-(C1-C6)-alkoxy-, phenyloxycarbonyloxy-(C1-C6)-alkoxy-, phenyl-(C1-C6)-alkoxycarbonyloxy-(C1-C6)-alkoxy-, amino, mono-((C1-C10)-alkyl)-amino-, di-((C1-C10)-alkyl)-amino- or R4R4Nxe2x80x94COxe2x80x94(C1-C6)-alkoxy- in which the residues R4 are independent of one another and can be identical or different;
R4 is hydrogen, (C1-C10)-alkyl, phenyl or phenyl-(C1-C8)-alkyl-;
R5 has one of the meanings of R4 with the exception of hydrogen;
phenyl which is contained in the group E is an unsubstituted phenyl residue or a phenyl residue which is substituted by one or more identical or different substituents from the group consisting of (C1-C4)-alkyl, (C1-C4)-alkoxy, methylenedioxy, ethylenedioxy, halogen, trifluoromethyl and trifluoromethoxy;
in all their stereoisomeric forms and mixtures thereof in all ratios,
and their physiologically acceptable salts.
The most preferred compounds include compounds of the formula I in which
R1 is hydrogen or methyl;
R2 is unsubstituted phenyl, phenyl which is substituted by a methylenedioxy residue or an ethylenedioxy residue, phenyl which is substituted by one or two methoxy groups, or (C1-C4)-alkyl;
X is xe2x80x94CH2xe2x80x94CH2xe2x80x94 or xe2x80x94CH2xe2x80x94CH2xe2x80x94CH2xe2x80x94, where one of the CH2 groups in these two residues can be replaced by a carbonyl group Cxe2x95x90O;
W is isopropyl or cyclopropyl;
V is hydrogen or methoxy;
E is xe2x80x94COxe2x80x94OH, xe2x80x94COxe2x80x94Oxe2x80x94(C1-C4)-alkyl, xe2x80x94COxe2x80x94NH2 or xe2x80x94CH2xe2x80x94OH;
in all their stereoisomeric forms and mixtures thereof in all ratios,
and their physiologically acceptable salts.
A subgroup of these compounds is formed by the compounds of the formula I in which
R1 is hydrogen or methyl;
R2 is phenyl which is substituted by a methylenedioxy residue or an ethylenedioxy residue, or phenyl which is substituted by one or two methoxy groups;
X is xe2x80x94CH2xe2x80x94CH2xe2x80x94 or xe2x80x94CH2xe2x80x94CH2xe2x80x94CH2xe2x80x94, where one of the CH2 groups in these two residues can be replaced by a carbonyl group Cxe2x95x90O;
W is isopropyl or cyclopropyl;
V is hydrogen or methoxy;
E is xe2x80x94COxe2x80x94OH, xe2x80x94COxe2x80x94Oxe2x80x94(C1-C4)-alkyl, xe2x80x94COxe2x80x94NH2 or xe2x80x94CH2xe2x80x94OH;
in all their stereoisomeric forms and mixtures thereof in all ratios,
and their physiologically acceptable salts.
A further subgroup of these compounds is formed by compounds of the formula I in which
R1 is hydrogen or methyl;
R2 is unsubstituted phenyl;
X is xe2x80x94CH2xe2x80x94CH2xe2x80x94 or xe2x80x94CH2xe2x80x94CH2xe2x80x94CH2xe2x80x94, where one of the CH2 groups in these two residues can be replaced by a carbonyl group Cxe2x95x90O;
W is isopropyl or cyclopropyl;
V is hydrogen or methoxy;
E is xe2x80x94COxe2x80x94OH, xe2x80x94COxe2x80x94Oxe2x80x94(C1-C4)-alkyl, xe2x80x94COxe2x80x94NH2 or xe2x80x94CH2xe2x80x94OH;
in all their stereoisomeric forms and mixtures thereof in all ratios,
and their physiologically acceptable salts.
A further subgroup of these compounds is formed by compounds of the formula I in which
R1 is hydrogen or methyl;
R2 is (C1-C4)-alkyl, preferably methyl;
X is xe2x80x94CH2xe2x80x94CH2xe2x80x94 or xe2x80x94CH2xe2x80x94CH2xe2x80x94CH2xe2x80x94, where one of the CH2 groups in these two residues can be replaced by a carbonyl group Cxe2x95x90O;
W is isopropyl or cyclopropyl;
V is hydrogen or methoxy;
E is xe2x80x94COxe2x80x94OH, xe2x80x94COxe2x80x94Oxe2x80x94(C1-C4)-alkyl, xe2x80x94COxe2x80x94NH2 or xe2x80x94CH2xe2x80x94OH;
in all their stereoisomeric forms and mixtures thereof in all ratios,
and their physiologically acceptable salts.
For the abovementioned embodiment of the invention in which the group V in the compounds of the formula I is hydrogen and the group W is isopropyl, that is for the compounds of the formula Ik, examples of specific compounds are indicated below each of which expressly is a subject of the present invention. The following abbreviations are used in the names of the compounds.
IBU=2-methylpropyl=isobutyl=xe2x80x94CHxe2x80x94CH2xe2x80x94CH(CH3)2 
4PM-3-PUB-DI=4,4-pentamethylene-3-(4-(3-phenylureido)benzyl)-2,5-dioxoimidazolidin-1-yl
4PM-3-MPUB-DI=4,4-pentamethylene-3-(4-(3-(2-methylphenyl)ureido)benzyl)-2,5-dioxoimidazolidin-1-yl
4TM-3-PUB-DI=4,4-tetramethylene-3-(4-(3-phenylureido)benzyl)-2,5-dioxoimidazolidin-1-yl
4TM-3-MPUB-DI=4,4-tetramethylene-3-(4-(3-(2-methylphenyl)ureido)benzyl)-2,5-dioxoimidazolidin-1-yl
4OPM-3-PUB-DI=4,4-(3-oxopentamethylene)-3-(4-(3-phenylureido)benzyl)-2,5-dioxoimidazolidin-1-yl
4OPM-3-MPUB-DI=4,4-(3-oxopentamethylene)-3-(4-(3-(2-methylphenyl)ureido)-benzyl)-2,5-dioxoimidazolidin-1-yl
4OTM-3-PUB-DI=4,4-(2-oxotetramethylene)-3-(4-(3-phenylureido)benzyl)-2,5-dioxoimidazolidin-1-yl
4OTM-3-MPUB-DI=4,4-(2-oxotetramethylene)-3-(4-(3-(2-methylphenyl)ureido)-benzyl)-2,5-dioxoimidazolidin-1-yl
A name such as, for example, 3-(2-(4OPM-3-MPUB-DI)-2-(IBU)-acetylamino)-3-(3,4-dimethoxyphenyl)propionamide is thus to be understood as meaning the compound 3-(2-(4,4-(3-oxopentamethylene)-3-(4-(3-(2-methylphenyl)ureido)benzyl)-2,5-dioxoimidazolidin-1-yl)-2-(2-methylpropyl)acetylamino)-3-(3,4-dimethoxyphenyl)propionamide of the formula Im. 
The present invention relates, for example, to the following compounds:
3-(2-(4PM-3-PUB-DI)-2-(IBU)-acetylamino)-3-methylpropionic acid
3-(2-(4PM-3-MPUB-DI)-2-(IBU)-acetylamino)-3-methylpropionic acid
3-(2-(4TM-3-PUB-DI)-2-(IBU)-acetylamino)-3-methylpropionic acid
3-(2-(4TM-3-MPUB-DI)-2-(IBU)-acetylamino)-3-methylpropionic acid
3-(2-(4OPM-3-PUB-DI)-2-(IBU)-acetylamino)-3-methylpropionic acid
3-(2-(4OPM-3-MPUB-DI)-2-(IBU)-acetylamino)-3-methylpropionic acid
3-(2-(4OTM-3-PUB-DI)-2-(IBU)-acetylamino)-3-methylpropionic acid
3-(2-(4OTM-3-MPUB-DI)-2-(IBU)-acetylamino)-3-methylpropionic acid
3-(2-(4PM-3-PUB-DI)-2-(IBU)-acetylamino)-3-methylpropionamide
3-(2-(4PM-3-MPUB-DI)-2-(IBU)-acetylamino)-3-methylpropionamide
3-(2-(4TM-3-PUB-DI)-2-(IBU)-acetylamino)-3-methylpropionamide
3-(2-(4TM-3-MPUB-DI)-2-(IBU)-acetylamino)-3-methylpropionamide
3-(2-(4OPM-3-PUB-DI)-2-(IBU)-acetylamino)-3-methylpropionamide
3-(2-(4OPM-3-MPUB-DI)-2-(IBU)-acetylamino)-3-methylpropionamide
3-(2-(4OTM-3-PUB-DI)-2-(IBU)-acetylamino)-3-methylpropionamide
3-(2-(4OTM-3-MPUB-DI)-2-(IBU)-acetylamino)-3-methylpropionamide
3-(2-(4PM-3-PUB-DI)-2-(IBU)-acetylamino)-3-methylpropanol
3-(2-(4PM-3-MPUB-DI)-2-(IBU)-acetylamino)-3-methylpropanol
3-(2-(4TM-3-PUB-DI)-2-(IBU)-acetylamino)-3-methylpropanol
3-(2-(4TM-3-MPUB-DI)-2-(IBU)-acetylamino)-3-methylpropanol
3-(2-(4OPM-3-PUB-DI)-2-(IBU)-acetylamino)-3-methylpropanol
3-(2-(4OPM-3-MPUB-DI)-2-(IBU)-acetylamino)-3-methylpropanol
3-(2-(4OTM-3-PUB-DI)-2-(IBU)-acetylamino)-3-methylpropanol
3-(2-(4OTM-3-MPUB-DI)-2-(IBU)-acetylamino)-3-methylpropanol
3-(2-(4PM-3-PUB-DI)-2-(IBU)-acetylamino)-3-(IBU)-propionic acid
3-(2-(4PM-3-MPUB-DI)-2-(IBU)-acetylamino)-3-(IBU)-propionic acid
3-(2-(4TM-3-PUB-DI)-2-(IBU)-acetylamino)-3-(IBU)-propionic acid
3-(2-(4TM-3-MPUB-DI)-2-(IBU)-acetylamino)-3-(IBU)-propionic acid
3-(2-(4OPM-3-PUB-DI)-2-(IBU)-acetylamino)-3-(IBU)-propionic acid
3-(2-(4OPM-3-MPUB-DI)-2-(IBU)-acetylamino)-3-(IBU)-propionic acid
3-(2-(4OTM-3-PUB-DI)-2-(IBU)-acetylamino)-3-(IBU)-propionic acid
3-(2-(4OTM-3-MPUB-DI)-2-(IBU)-acetylamino)-3-(IBU)-propionic acid
3-(2-(4PM-3-PUB-DI)-2-(IBU)-acetylamino)-3-(IBU)-propionamide
3-(2-(4PM-3-MPUB-DI)-2-(IBU)-acetylamino)-3-(IBU)-propionamide
3-(2-(4TM-3-PUB-DI)-2-(IBU)-acetylamino)-3-(IBU)-propionamide
3-(2-(4TM-3-MPUB-DI)-2-(IBU)-acetylamino)-3-(IBU)-propionamide
3-(2-(4OPM-3-PUB-DI)-2-(IBU)-acetylamino)-3-(IBU)-propionamide
3-(2-(4OPM-3-MPUB-DI)-2-(IBU)-acetylamino)-3-(IBU)-propionamide
3-(2-(4OTM-3-PUB-DI)-2-(IBU)-acetylamino)-3-(IBU)-propionamide
3-(2-(4OTM-3-MPUB-DI)-2-(IBU)-acetylamino)-3-(IBU)-propionamide
3-(2-(4PM-3-PUB-DI)-2-(IBU)-acetylamino)-3-(IBU)-propanol
3-(2-(4PM-3-MPUB-DI)-2-(IBU)-acetylamino)-3-(IBU)-propanol
3-(2-(4TM-3-PUB-DI)-2-(IBU)-acetylamino)-3-(IBU)-propanol
3-(2-(4TM-3-MPUB-DI)-2-(IBU)-acetylamino)-3-(IBU)-propanol
3-(2-(4OPM-3-PUB-DI)-2-(IBU)-acetylamino)-3-(IBU)-propanol
3-(2-(4OPM-3-MPUB-DI)-2-(IBU)-acetylamino)-3-(IBU)-propanol
3-(2-(4OTM-3-PUB-DI)-2-(IBU)-acetylamino)-3-(IBU)-propanol
3-(2-(4OTM-3-MPUB-DI)-2-(IBU)-acetylamino)-3-(IBU)-propanol
3-(2-(4PM-3-PUB-DI)-2-(IBU)-acetylamino)-3-phenylpropionic acid
3-(2-(4PM-3-MPUB-DI)-2-(IBU)-acetylamino)-3-phenylpropionic acid
3-(2-(4TM-3-PUB-DI)-2-(IBU)-acetylamino)-3-phenylpropionic acid
3-(2-(4TM-3-MPUB-DI)-2-(IBU)-acetylamino)-3-phenylpropionic acid
3-(2-(4OPM-3-PUB-DI)-2-(IBU)-acetylamino)-3-phenylpropionic acid
3-(2-(4OPM-3-MPUB-DI)-2-(IBU)-acetylamino)-3-phenylpropionic acid
3-(2-(4OTM-3-PUB-DI)-2-(IBU)-acetylamino)-3-phenylpropionic acid
3-(2-(4OTM-3-MPUB-DI)-2-(IBU)-acetylamino)-3-phenylpropionic acid
3-(2-(4PM-3-PUB-DI)-2-(IBU)-acetylamino)-3-phenylpropionamide
3-(2-(4PM-3-MPUB-DI)-2-(IBU)-acetylamino)-3-phenylpropionamide
3-(2-(4TM-3-PUB-DI)-2-(IBU)-acetylamino)-3-phenylpropionamide
3-(2-(4TM-3-MPUB-DI)-2-(IBU)-acetylamino)-3-phenylpropionamide
3-(2-(4OPM-3-PUB-DI)-2-(IBU)-acetylamino)-3-phenylpropionamide
3-(2-(4OPM-3-MPUB-DI)-2-(IBU)-acetylamino)-3-phenylpropionamide
3-(2-(4OTM-3-PUB-DI)-2-(IBU)-acetylamino)-3-phenylpropionamide
3-(2-(4OTM-3-MPUB-DI)-2-(IBU)-acetylamino)-3-phenylpropionamide
3-(2-(4PM-3-PUB-DI)-2-(IBU)-acetylamino)-3-phenylpropanol
3-(2-(4PM-3-MPUB-DI)-2-(IBU)-acetylamino)-3-phenylpropanol
3-(2-(4TM-3-PUB-DI)-2-(IBU)-acetylamino)-3-phenylpropanol
3-(2-(4TM-3-MPUB-DI)-2-(IBU)-acetylamino)-3-phenylpropanol
3-(2-(4OPM-3-PUB-DI)-2-(IBU)-acetylamino)-3-phenylpropanol
3-(2-(4OPM-3-MPUB-DI)-2-(IBU)-acetylamino)-3-phenylpropanol
3-(2-(4OTM-3-PUB-DI)-2-(IBU)-acetylamino)-3-phenylpropanol
3-(2-(4OTM-3-MPUB-DI)-2-(IBU)-acetylamino)-3-phenylpropanol
3-(2-(4PM-3-PUB-DI)-2-(IBU)-acetylamino)-3-(2-methoxyphenyl)propionic acid
3-(2-(4PM-3-MPUB-DI)-2-(IBU)-acetylamino)-3-(2-methoxyphenyl)propionic acid
3-(2-(4TM-3-PUB-DI)-2-(IBU)-acetylamino)-3-(2-methoxyphenyl)propionic acid
3-(2-(4TM-3-MPUB-DI)-2-(IBU)-acetylamino)-3-(2-methoxyphenyl)propionic acid
3-(2-(4OPM-3-PUB-DI)-2-(IBU)-acetylamino)-3-(2-methoxyphenyl)propionic acid
3-(2-(4OPM-3-MPUB-DI)-2-(IBU)-acetylamino)-3-(2-methoxyphenyl)propionic acid
3-(2-(4OTM-3-PUB-DI)-2-(IBU)-acetylamino)-3-(2-methoxyphenyl)propionic acid
3-(2-(4OTM-3-MPUB-DI)-2-(IBU)-acetylamino)-3-(2-methoxyphenyl)propionic acid
3-(2-(4PM-3-PUB-DI)-2-(IBU)-acetylamino)-3-(2-methoxyphenyl)propionamide
3-(2-(4PM-3-MPUB-DI)-2-(IBU)-acetylamino)-3-(2-methoxyphenyl)propionamide
3-(2-(4TM-3-PUB-DI)-2-(IBU)-acetylamino)-3-(2-methoxyphenyl)propionamide
3-(2-(4TM-3-MPUB-DI)-2-(IBU)-acetylamino)-3-(2-methoxyphenyl)propionamide
3-(2-(4OPM-3-PUB-DI)-2-(IBU)-acetylamino)-3-(2-methoxyphenyl)propionamide
3-(2-(4OPM-3-MPUB-DI)-2-(IBU)-acetylamino)-3-(2-methoxyphenyl)propionamide
3-(2-(4OTM-3-PUB-DI)-2-(IBU)-acetylamino)-3-(2-methoxyphenyl)propionamide
3-(2-(4OTM-3-MPUB-DI)-2-(IBU)-acetylamino)-3-(2-methoxyphenyl)propionamide
3-(2-(4PM-3-PUB-DI)-2-(IBU)-acetylamino)-3-(2-methoxyphenyl)propanol
3-(2-(4PM-3-MPUB-DI)-2-(IBU)-acetylamino)-3-(2-methoxyphenyl)propanol
3-(2-(4TM-3-PUB-DI)-2-(IBU)-acetylamino)-3-(2-methoxyphenyl)propanol
3-(2-(4TM-3-MPUB-DI)-2-(IBU)-acetylamino)-3-(2-methoxyphenyl)propanol
3-(2-(4OPM-3-PUB-DI)-2-(IBU)-acetylamino)-3-(2-methoxyphenyl)propanol
3-(2-(4OPM-3-MPUB-DI)-2-(IBU)-acetylamino)-3-(2-methoxyphenyl)propanol
3-(2-(4OTM-3-PUB-DI)-2-(IBU)-acetylamino)-3-(2-methoxyphenyl)propanol
3-(2-(4OTM-3-MPUB-DI)-2-(IBU)-acetylamino)-3-(2-methoxyphenyl)propanol
3-(2-(4PM-3-PUB-DI)-2-(IBU)-acetylamino)-3-(3-methoxyphenyl)propionic acid
3-(2-(4PM-3-MPUB-DI)-2-(IBU)-acetylamino)-3-(3-methoxyphenyl)propionic acid
3-(2-(4TM-3-PUB-DI)-2-(IBU)-acetylamino)-3-(3-methoxyphenyl)propionic acid
3-(2-(4TM-3-MPUB-DI)-2-(IBU)-acetylamino)-3-(3-methoxyphenyl)propionic acid
3-(2-(4OPM-3-PUB-DI)-2-(IBU)-acetylamino)-3-(3-methoxyphenyl)propionic acid
3-(2-(4OPM-3-MPUB-DI)-2-(IBU)-acetylamino)-3-(3-methoxyphenyl)propionic acid
3-(2-(4OTM-3-PUB-DI)-2-(IBU)-acetylamino)-3-(3-methoxyphenyl)propionic acid
3-(2-(4OTM-3-MPUB-DI)-2-(IBU)-acetylamino)-3-(3-methoxyphenyl)propionic acid
3-(2-(4PM-3-PUB-DI)-2-(IBU)-acetylamino)-3-(3-methoxyphenyl)propionamide
3-(2-(4PM-3-MPUB-DI)-2-(IBU)-acetylamino)-3-(3-methoxyphenyl)propionamide
3-(2-(4TM-3-PUB-DI)-2-(IBU)-acetylamino)-3-(3-methoxyphenyl)propionamide
3-(2-(4TM-3-MPUB-DI)-2-(IBU)-acetylamino)-3-(3-methoxyphenyl)propionamide
3-(2-(4OPM-3-PUB-DI)-2-(IBU)-acetylamino)-3-(3-methoxyphenyl)propionamide
3-(2-(4OPM-3-MPUB-DI)-2-(IBU)-acetylamino)-3-(3-methoxyphenyl)propionamide
3-(2-(4OTM-3-PUB-DI)-2-(IBU)-acetylamino)-3-(3-methoxyphenyl)propionamide
3-(2-(4OTM-3-MPUB-DI)-2-(IBU)-acetylamino)-3-(3-methoxyphenyl)propionamide
3-(2-(4PM-3-PUB-DI)-2-(IBU)-acetylamino)-3-(3-methoxyphenyl)propanol
3-(2-(4PM-3-MPUB-DI)-2-(IBU)-acetylamino)-3-(3-methoxyphenyl)propanol
3-(2-(4TM-3-PUB-DI)-2-(IBU)-acetylamino)-3-(3-methoxyphenyl)propanol
3-(2-(4TM-3-MPUB-DI)-2-(IBU)-acetylamino)-3-(3-methoxyphenyl)propanol
3-(2-(4OPM-3-PUB-DI)-2-(IBU)-acetylamino)-3-(3-methoxyphenyl)propanol
3-(2-(4OPM-3-MPUB-DI)-2-(IBU)-acetylamino)-3-(3-methoxyphenyl)propanol
3-(2-(4OTM-3-PUB-DI)-2-(IBU)-acetylamino)-3-(3-methoxyphenyl)propanol
3-(2-(4OTM-3-MPUB-DI)-2-(IBU)-acetylamino)-3-(3-methoxyphenyl)propanol
3-(2-(4PM-3-PUB-DI)-2-(IBU)-acetylamino)-3-(4-methoxyphenyl)propionic acid
3-(2-(4PM-3-MPUB-DI)-2-(IBU)-acetylamino)-3-(4-methoxyphenyl)propionic acid
3-(2-(4TM-3-PUB-DI)-2-(IBU)-acetylamino)-3-(4-methoxyphenyl)propionic acid
3-(2-(4TM-3-MPUB-DI)-2-(IBU)-acetylamino)-3-(4-methoxyphenyl)propionic acid
3-(2-(4OPM-3-PUB-DI)-2-(IBU)-acetylamino)-3-(4-methoxyphenyl)propionic acid
3-(2-(4OPM-3-MPUB-DI)-2-(IBU)-acetylamino)-3-(4-methoxyphenyl)propionic acid
3-(2-(4OTM-3-PUB-DI)-2-(IBU)-acetylamino)-3-(4-methoxyphenyl)propionic acid
3-(2-(4OTM-3-MPUB-DI)-2-(IBU)-acetylamino)-3-(4-methoxyphenyl)propionic acid
3-(2-(4PM-3-PUB-DI)-2-(IBU)-acetylamino)-3-(4-methoxyphenyl)propionamide
3-(2-(4PM-3-MPUB-DI)-2-(IBU)-acetylamino)-3-(4-methoxyphenyl)propionamide
3-(2-(4TM-3-PUB-DI)-2-(IBU)-acetylamino)-3-(4-methoxyphenyl)propionamide
3-(2-(4TM-3-MPUB-DI)-2-(IBU)-acetylamino)-3-(4-methoxyphenyl)propionamide
3-(2-(4OPM-3-PUB-DI)-2-(IBU)-acetylamino)-3-(4-methoxyphenyl)propionamide
3-(2-(4OPM-3-MPUB-DI)-2-(IBU)-acetylamino)-3-(4-methoxyphenyl)propionamide
3-(2-(4OTM-3-PUB-DI)-2-(IBU)-acetylamino)-3-(4-methoxyphenyl)propionamide
3-(2-(4OTM-3-MPUB-DI)-2-(IBU)-acetylamino)-3-(4-methoxyphenyl)propionamide
3-(2-(4PM-3-PUB-DI)-2-(IBU)-acetylamino)-3-(4-methoxyphenyl)propanol
3-(2-(4PM-3-MPUB-DI)-2-(IBU)-acetylamino)-3-(4-methoxyphenyl)propanol
3-(2-(4TM-3-PUB-DI)-2-(IBU)-acetylamino)-3-(4-methoxyphenyl)propanol
3-(2-(4TM-3-MPUB-DI)-2-(IBU)-acetylamino)-3-(4-methoxyphenyl)propanol
3-(2-(4OPM-3-PUB-DI)-2-(IBU)-acetylamino)-3-(4-methoxyphenyl)propanol
3-(2-(4OPM-3-MPUB-DI)-2-(IBU)-acetylamino)-3-(4-methoxyphenyl)propanol
3-(2-(4OTM-3-PUB-DI)-2-(IBU)-acetylamino)-3-(4-methoxyphenyl)propanol
3-(2-(4OTM-3-MPUB-DI)-2-(IBU)-acetylamino)-3-(4-methoxyphenyl)propanol
3-(2-(4PM-3-PUB-DI)-2-(IBU)-acetylamino)-3-(2,3-dimethoxyphenyl)propionic acid
3-(2-(4PM-3-MPUB-DI)-2-(IBU)-acetylamino)-3-(2,3-dimethoxyphenyl)propionic acid
3-(2-(4TM-3-PUB-DI)-2-(IBU)-acetylamino)-3-(2,3-dimethoxyphenyl)propionic acid
3-(2-(4TM-3-MPUB-DI)-2-(IBU)-acetylamino)-3-(2,3-dimethoxyphenyl)propionic acid
3-(2-(4OPM-3-PUB-DI)-2-(IBU)-acetylamino)-3-(2,3-dimethoxyphenyl)propionic acid
3-(2-(4OPM-3-MPUB-DI)-2-(IBU)-acetylamino)-3-(2,3-dimethoxyphenyl)propionic acid
3-(2-(4OTM-3-PUB-DI)-2-(IBU)-acetylamino)-3-(2,3-dimethoxyphenyl)propionic acid
3-(2-(4OTM-3-MPUB-DI)-2-(IBU)-acetylamino)-3-(2,3-dimethoxyphenyl)propionic acid
3-(2-(4PM-3-PUB-DI)-2-(IBU)-acetylamino)-3-(2,3-dimethoxyphenyl)propionamide
3-(2-(4PM-3-MPUB-DI)-2-(IBU)-acetylamino)-3-(2,3-dimethoxyphenyl)propionamide
3-(2-(4TM-3-PUB-DI)-2-(IBU)-acetylamino)-3-(2,3-dimethoxyphenyl)propionamide
3-(2-(4TM-3-MPUB-DI)-2-(IBU)-acetylamino)-3-(2,3-dimethoxyphenyl)propionamide
3-(2-(4OPM-3-PUB-DI)-2-(IBU)-acetylamino)-3-(2,3-dimethoxyphenyl)propionamide
3-(2-(4OPM-3-MPUB-DI)-2-(IBU)-acetylamino)-3-(2,3-dimethoxyphenyl)propionamide
3-(2-(4OTM-3-PUB-DI)-2-(IBU)-acetylamino)-3-(2,3-dimethoxyphenyl)propionamide
3-(2-(4OTM-3-MPUB-DI)-2-(IBU)-acetylamino)-3-(2,3-dimethoxyphenyl)propionamide
3-(2-(4PM-3-PUB-DI)-2-(IBU)-acetylamino)-3-(2,3-dimethoxyphenyl)propanol
3-(2-(4PM-3-MPUB-DI)-2-(IBU)-acetylamino)-3-(2,3-dimethoxyphenyl)propanol
3-(2-(4TM-3-PUB-DI)-2-(IBU)-acetylamino)-3-(2,3-dimethoxyphenyl)propanol
3-(2-(4TM-3-MPUB-DI)-2-(IBU)-acetylamino)-3-(2,3-dimethoxyphenyl)propanol
3-(2-(4OPM-3-PUB-DI)-2-(IBU)-acetylamino)-3-(2,3-dimethoxyphenyl)propanol
3-(2-(4OPM-3-MPUB-DI)-2-(IBU)-acetylamino)-3-(2,3-dimethoxyphenyl)propanol
3-(2-(4OTM-3-PUB-DI)-2-(IBU)-acetylamino)-3-(2,3-dimethoxyphenyl)propanol
3-(2-(4OTM-3-MPUB-DI)-2-(IBU)-acetylamino)-3-(2,3-dimethoxyphenyl)propanol
3-(2-(4PM-3-MPUB-DI)-2-(IBU)-acetylamino)-3-(2,4-dimethoxyphenyl)propionic acid
3-(2-(4PM-3-MPUB-DI)-2-(IBU)-acetylamino)-3-(2,4-dimethoxyphenyl)propionic acid
3-(2-(4TM-3-PUB-DI)-2-(IBU)-acetylamino)-3-(2,4-dimethoxyphenyl)propionic acid
3-(2-(4TM-3-MPUB-DI)-2-(IBU)-acetylamino)-3-(2,4-dimethoxyphenyl)propionic acid
3-(2-(4OPM-3-PUB-DI)-2-(IBU)-acetylamino)-3-(2,4-dimethoxyphenyl)propionic acid
3-(2-(4OPM-3-PUB-DI)-2-(IBU)-acetylamino)-3-(2,4-dimethoxyphenyl)propionic acid
3-(2-(4OTM-3-PUB-DI)-2-(IBU)-acetylamino)-3-(2,4-dimethoxyphenyl)propionic acid
3-(2-(4OTM-3-MPUB-DI)-2-(IBU)-acetylamino)-3-(2,4-dimethoxyphenyl)propionic acid
3-(2-(4PM-3-PUB-DI)-2-(IBU)-acetylamino)-3-(2,4-dimethoxyphenyl)propionamide
3-(2-(4PM-3-MPUB-DI)-2-(IBU)-acetylamino)-3-(2,4-dimethoxyphenyl)propionamide
3-(2-(4TM-3-PUB-DI)-2-(IBU)-acetylamino)-3-(2,4-dimethoxyphenyl)propionamide
3-(2-(4TM-3-MPUB-DI)-2-(IBU)-acetylamino)-3-(2,4-dimethoxyphenyl)propionamide
3-(2-(4OPM-3-PUB-DI)-2-(IBU)-acetylamino)-3-(2,4-dimethoxyphenyl)propionamide
3-(2-(4OPM-3-MPUB-DI)-2-(IBU)-acetylamino)-3-(2,4-dimethoxyphenyl)propionamide
3-(2-(4OTM-3-PUB-DI)-2-(IBU)-acetylamino)-3-(2,4-dimethoxyphenyl)propionamide
3-(2-(4OTM-3-MPUB-DI)-2-(IBU)-acetylamino)-3-(2,4-dimethoxyphenyl)propionamide
3-(2-(4PM-3-PUB-DI)-2-(IBU)-acetylamino)-3-(2,4-dimethoxyphenyl)propanol
3-(2-(4PM-3-MPUB-DI)-2-(IBU)-acetylamino)-3-(2,4-dimethoxyphenyl)propanol
3-(2-(4TM-3-PUB-DI)-2-(IBU)-acetylamino)-3-(2,4-dimethoxyphenyl)propanol
3-(2-(4TM-3-MPUB-DI)-2-(IBU)-acetylamino)-3-(2,4-dimethoxyphenyl)propanol
3-(2-(4OPM-3-PUB-DI)-2-(IBU)-acetylamino)-3-(2,4-dimethoxyphenyl)propanol
3-(2-(4OPM-3-MPUB-DI)-2-(IBU)-acetylamino)-3-(2,4-dimethoxyphenyl)propanol
3-(2-(4OTM-3-PUB-DI)-2-(IBU)-acetylamino)-3-(2,4-dimethoxyphenyl)propanol
3-(2-(4OTM-3-MPUB-DI)-2-(IBU)-acetylamino)-3-(2,4-dimethoxyphenyl)propanol
3-(2-(4PM-3-PUB-DI)-2-(IBU)-acetylamino)-3-(2,5-dimethoxyphenyl)propionic acid
3-(2-(4PM-3-MPUB-DI)-2-(IBU)-acetylamino)-3-(2,5-dimethoxyphenyl)propionic acid
3-(2-(4TM-3-PUB-DI)-2-(IBU)-acetylamino)-3-(2,5-dimethoxyphenyl)propionic acid
3-(2-(4TM-3-MPUB-DI)-2-(IBU)-acetylamino)-3-(2,5-dimethoxyphenyl)propionic acid
3-(2-(4OPM-3-PUB-DI)-2-(IBU)-acetylamino)-3-(2,5-dimethoxyphenyl)propionic acid
3-(2-(4OPM-3-MPUB-DI)-2-(IBU)-acetylamino)-3-(2,5-dimethoxyphenyl)propionic acid
3-(2-(4OTM-3-PUB-DI)-2-(IBU)-acetylamino)-3-(2,5-dimethoxyphenyl)propionic acid
3-(2-(4OTM-3-MPUB-DI)-2-(IBU)-acetylamino)-3-(2,5-dimethoxyphenyl)propionic acid
3-(2-(4PM-3-PUB-DI)-2-(IBU)-acetylamino)-3-(2,5-dimethoxyphenyl)propionamide
3-(2-(4PM-3-MPUB-DI)-2-(IBU)-acetylamino)-3-(2,5-dimethoxyphenyl)propionamide
3-(2-(4TM-3-PUB-DI)-2-(IBU)-acetylamino)-3-(2,5-dimethoxyphenyl)propionamide
3-(2-(4TM-3-MPUB-DI)-2-(IBU)-acetylamino)-3-(2,5-dimethoxyphenyl)propionamide
3-(2-(4OPM-3-PUB-DI)-2-(IBU)-acetylamino)-3-(2,5-dimethoxyphenyl)propionamide
3-(2-(4OPM-3-MPUB-DI)-2-(IBU)-acetylamino)-3-(2,5-dimethoxyphenyl)propionamide
3-(2-(4OTM-3-PUB-DI)-2-(IBU)-acetylamino)-3-(2,5-dimethoxyphenyl)propionamide
3-(2-(4OTM-3-MPUB-DI)-2-(IBU)-acetylamino)-3-(2,5-dimethoxyphenyl)propionamide
3-(2-(4PM-3-PUB-DI)-2-(IBU)-acetylamino)-3-(2,5-dimethoxyphenyl)propanol
3-(2-(4PM-3-MPUB-DI)-2-(IBU)-acetylamino)-3-(2,5-dimethoxyphenyl)propanol
3-(2-(4TM-3-PUB-DI)-2-(IBU)-acetylamino)-3-(2,5-dimethoxyphenyl)propanol
3-(2-(4TM-3-MPUB-DI)-2-(IBU)-acetylamino)-3-(2,5-dimethoxyphenyl)propanol
3-(2-(4OPM-3-PUB-DI)-2-(IBU)-acetylamino)-3-(2,5-dimethoxyphenyl)propanol
3-(2-(4OPM-3-MPUB-DI)-2-(IBU)-acetylamino)-3-(2,5-dimethoxyphenyl)propanol
3-(2-(4OTM-3-PUB-DI)-2-(IBU)-acetylamino)-3-(2,5-dimethoxyphenyl)propanol
3-(2-(4OTM-3-MPUB-DI)-2-(IBU)-acetylamino)-3-(2,5-dimethoxyphenyl)propanol
3-(2-(4PM-3-PUB-DI)-2-(IBU)-acetylamino)-3-(2,6-dimethoxyphenyl)propionic acid
3-(2-(4PM-3-MPUB-DI)-2-(IBU)-acetylamino)-3-(2,6-dimethoxyphenyl)propionic acid
3-(2-(4TM-3-PUB-DI)-2-(IBU)-acetylamino)-3-(2,6-dimethoxyphenyl)propionic acid
3-(2-(4TM-3-MPUB-DI)-2-(IBU)-acetylamino)-3-(2,6-dimethoxyphenyl)propionic acid
3-(2-(4OPM-3-PUB-DI)-2-(IBU)-acetylamino)-3-(2,6-dimethoxyphenyl)propionic acid
3-(2-(4OPM-3-MPUB-DI)-2-(IBU)-acetylamino)-3-(2,6-dimethoxyphenyl)propionic acid
3-(2-(4OTM-3-PUB-DI)-2-(IBU)-acetylamino)-3-(2,6-dimethoxyphenyl)propionic acid
3-(2-(4OTM-3-MPUB-DI)-2-(IBU)-acetylamino)-3-(2,6-dimethoxyphenyl)propionic acid
3-(2-(4PM-3-PUB-DI)-2-(IBU)-acetylamino)-3-(2,6-dimethoxyphenyl)propionamide
3-(2-(4PM-3-MPUB-DI)-2-(IBU)-acetylamino)-3-(2,6-dimethoxyphenyl)propionamide
3-(2-(4TM-3-PUB-DI)-2-(IBU)-acetylamino)-3-(2,6-dimethoxyphenyl)propionamide
3-(2-(4TM-3-MPUB-DI)-2-(IBU)-acetylamino)-3-(2,6-dimethoxyphenyl)propionamide
3-(2-(4OPM-3-PUB-DI)-2-(IBU)-acetylamino)-3-(2,6-dimethoxyphenyl)propionamide
3-(2-(4OPM-3-MPUB-DI)-2-(IBU)-acetylamino)-3-(2,6-dimethoxyphenyl)propionamide
3-(2-(4OTM-3-PUB-DI)-2-(IBU)-acetylamino)-3-(2,6-dimethoxyphenyl)propionamide
3-(2-(4OTM-3-MPUB-DI)-2-(IBU)-acetylamino)-3-(2,6-dimethoxyphenyl)propionamide
3-(2-(4PM-3-PUB-DI)-2-(IBU)-acetylamino)-3-(2,6-dimethoxyphenyl)propanol
3-(2-(4PM-3-MPUB-DI)-2-(IBU)-acetylamino)-3-(2,6-dimethoxyphenyl)propanol
3-(2-(4TM-3-PUB-DI)-2-(IBU)-acetylamino)-3-(2,6-dimethoxyphenyl)propanol
3-(2-(4TM-3-MPUB-DI)-2-(IBU)-acetylamino)-3-(2,6-dimethoxyphenyl)propanol
3-(2-(4OPM-3-PUB-DI)-2-(IBU)-acetylamino)-3-(2,6-dimethoxyphenyl)propanol
3-(2-(4OPM-3-MPUB-DI)-2-(IBU)-acetylamino)-3-(2,6-dimethoxyphenyl)propanol
3-(2-(4OTM-3-PUB-DI)-2-(IBU)-acetylamino)-3-(2,6-dimethoxyphenyl)propanol
3-(2-(4OTM-3-MPUB-DI)-2-(IBU)-acetylamino)-3-(2,6-dimethoxyphenyl)propanol
3-(2-(4PM-3-PUB-DI)-2-(IBU)-acetylamino)-3-(3,4-dimethoxyphenyl)propionic acid
3-(2-(4PM-3-MPUB-DI)-2-(IBU)-acetylamino)-3-(3,4-dimethoxyphenyl)propionic acid
3-(2-(4TM-3-PUB-DI)-2-(IBU)-acetylamino)-3-(3,4-dimethoxyphenyl)propionic acid
3-(2-(4TM-3-MPUB-DI)-2-(IBU)-acetylamino)-3-(3,4-dimethoxyphenyl)propionic acid
3-(2-(4OPM-3-PUB-DI)-2-(IBU)-acetylamino)-3-(3,4-dimethoxyphenyl)propionic acid
3-(2-(4OPM-3-MPUB-DI)-2-(IBU)-acetylamino)-3-(3,4-dimethoxyphenyl)propionic acid
3-(2-(4OTM-3-PUB-DI)-2-(IBU)-acetylamino)-3-(3,4-dimethoxyphenyl)propionic acid
3-(2-(4OTM-3-MPUB-DI)-2-(IBU)-acetylamino)-3-(3,4-dimethoxyphenyl)propionic acid
3-(2-(4PM-3-PUB-DI)-2-(IBU)-acetylamino)-3-(3,4-dimethoxyphenyl)propionamide
3-(2-(4PM-3-MPUB-DI)-2-(IBU)-acetylamino)-3-(3,4-dimethoxyphenyl)propionamide
3-(2-(4TM-3-PUB-DI)-2-(IBU)-acetylamino)-3-(3,4-dimethoxyphenyl)propionamide
3-(2-(4TM-3-MPUB-DI)-2-(IBU)-acetylamino)-3-(3,4-dimethoxyphenyl)propionamide
3-(2-(4OPM-3-PUB-DI)-2-(IBU)-acetylamino)-3-(3,4-dimethoxyphenyl)propionamide
3-(2-(4OPM-3-MPUB-DI)-2-(IBU)-acetylamino)-3-(3,4-dimethoxyphenyl)propionamide
3-(2-(4OTM-3-PUB-DI)-2-(IBU)-acetylamino)-3-(3,4-dimethoxyphenyl)propionamide
3-(2-(4OTM-3-MPUB-DI)-2-(IBU)-acetylamino)-3-(3,4-dimethoxyphenyl)propionamide
3-(2-(4PM-3-PUB-DI)-2-(IBU)-acetylamino)-3-(3,4-dimethoxyphenyl)propanol
3-(2-(4PM-3-MPUB-DI)-2-(IBU)-acetylamino)-3-(3,4-dimethoxyphenyl)propanol
3-(2-(4TM-3-PUB-DI)-2-(IBU)-acetylamino)-3-(3,4-dimethoxyphenyl)propanol
3-(2-(4TM-3-MPUB-DI)-2-(IBU)-acetylamino)-3-(3,4-dimethoxyphenyl)propanol
3-(2-(4PM-3-PUB-DI)-2-(IBU)-acetylamino)-3-(3,4-dimethoxyphenyl)propanol
3-(2-(4OPM-3-MPUB-DI)-2-(IBU)-acetylamino)-3-(3,4-dimethoxyphenyl)propanol
3-(2-(4OTM-3-PUB-DI)-2-(IBU)-acetylamino)-3-(3,4-dimethoxyphenyl)propanol
3-(2-(4OTM-3-MPUB-DI)-2-(IBU)-acetylamino)-3-(3,4-dimethoxyphenyl)propanol
3-(2-(4PM-3-PUB-DI)-2-(IBU)-acetylamino)-3-(3,5-dimethoxyphenyl)propionic acid
3-(2-(4PM-3-MPUB-DI)-2-(IBU)-acetylamino)-3-(3,5-dimethoxyphenyl)propionic acid
3-(2-(4TM-3-PUB-DI)-2-(IBU)-acetylamino)-3-(3,5-dimethoxyphenyl)propionic acid
3-(2-(4TM-3-MPUB-DI)-2-(IBU)-acetylamino)-3-(3,5-dimethoxyphenyl)propionic acid
3-(2-(4OPM-3-PUB-DI)-2-(IBU)-acetylamino)-3-(3,5-dimethoxyphenyl)propionic acid
3-(2-(4OPM-3-MPUB-DI)-2-(IBU)-acetylamino)-3-(3,5-dimethoxyphenyl)propionic acid
3-(2-(4OTM-3-PUB-DI)-2-(IBU)-acetylamino)-3-(3,5-dimethoxyphenyl)propionic acid
3-(2-(4OTM-3-MPUB-DI)-2-(IBU)-acetylamino)-3-(3,5-dimethoxyphenyl)propionic acid
3-(2-(4PM-3-PUB-DI)-2-(IBU)-acetylamino)-3-(3,5-dimethoxyphenyl)propionamide
3-(2-(4PM-3-MPUB-DI)-2-(IBU)-acetylamino)-3-(3,5-dimethoxyphenyl)propionamide
3-(2-(4TM-3-PUB-DI)-2-(IBU)-acetylamino)-3-(3,5-dimethoxyphenyl)propionamide
3-(2-(4TM-3-MPUB-DI)-2-(IBU)-acetylamino)-3-(3,5-dimethoxyphenyl)propionamide
3-(2-(4OPM-3-PUB-DI)-2-(IBU)-acetylamino)-3-(3,5-dimethoxyphenyl)propionamide
3-(2-(4OPM-3-PUB-DI)-2-(IBU)-acetylamino)-3-(3,5-dimethoxyphenyl)propionamide
3-(2-(4OTM-3-PUB-DI)-2-(IBU)-acetylamino)-3-(3,5-dimethoxyphenyl)propionamide
3-(2-(4OPM-3-MPUB-DI)-2-(IBU)-acetylamino)-3-(3,5-dimethoxyphenyl)propionamide
3-(2-(4PM-3-PUB-DI)-2-(IBU)-acetylamino)-3-(3,5-dimethoxyphenyl)propanol
3-(2-(4PM-3-MPUB-DI)-2-(IBU)-acetylamino)-3-(3,5-dimethoxyphenyl)propanol
3-(2-(4TM-3-PUB-DI)-2-(IBU)-acetylamino)-3-(3,5-dimethoxyphenyl)propanol
3-(2-(4TM-3-MPUB-DI)-2-(IBU)-acetylamino)-3-(3,5-dimethoxyphenyl)propanol
3-(2-(4OPM-3-PUB-DI)-2-(IBU)-acetylamino)-3-(3,5-dimethoxyphenyl)propanol
3-(2-(4OPM-3-MPUB-DI)-2-(IBU)-acetylamino)-3-(3,5-dimethoxyphenyl)propanol
3-(2-(4OTM-3-PUB-DI)-2-(IBU)-acetylamino)-3-(3,5-dimethoxyphenyl)propanol
3-(2-(4OTM-3-MPUB-DI)-2-(IBU)-acetylamino)-3-(3,5-dimethoxyphenyl)propanol
3-(2-(4PM-3-PUB-DI)-2-(IBU)-acetylamino)-3-(3,4-methylenedioxyphenyl)propionic acid
3-(2-(4PM-3-MPUB-DI)-2-(IBU)-acetylamino)-3-(3,4-methylenedioxyphenyl)propionic acid
3-(2-(4TM-3-PUB-DI)-2-(IBU)-acetylamino)-3-(3,4-methylenedioxyphenyl)propionic acid
3-(2-(4TM-3-MPUB-DI)-2-(IBU)-acetylamino)-3-(3,4-methylenedioxyphenyl)propionic acid
3-(2-(4OPM-3-PUB-DI)-2-(IBU)-acetylamino)-3-(3,4-methylenedioxyphenyl)propionic acid
3-(2-(4OPM-3-MPUB-DI)-2-(IBU)-acetylamino)-3-(3,4-methylenedioxyphenyl)propionic acid
3-(2-(4OTM-3-PUB-DI)-2-(IBU)-acetylamino)-3-(3,4-methylenedioxyphenyl)propionic acid
3-(2-(4OTM-3-MPUB-DI)-2-(IBU)-acetylamino)-3-(3,4-methylenedioxyphenyl)propionic acid
3-(2-(4PM-3-PUB-DI)-2-(IBU)-acetylamino)-3-(3,4-methylenedioxyphenyl)propionamide
3-(2-(4PM-3-MPUB-DI)-2-(IBU)-acetylamino)-3-(3,4-methylenedioxyphenyl)propionamide
3-(2-(4TM-3-PUB-DI)-2-(IBU)-acetylamino)-3-(3,4-methylenedioxyphenyl)propionamide
3-(2-(4TM-3-MPUB-DI)-2-(IBU)-acetylamino)-3-(3,4-methylenedioxyphenyl)propionamide
3-(2-(4OPM-3-PUB-DI)-2-(IBU)-acetylamino)-3-(3,4-methylenedioxyphenyl)propionamide
3-(2-(4OPM-3-MPUB-DI)-2-(IBU)-acetylamino)-3-(3,4-methylenedioxyphenyl)propionamide
3-(2-(4OTM-3-PUB-DI)-2-(IBU)-acetylamino)-3-(3,4-methylenedioxyphenyl)propionamide
3-(2-(4OTM-3-MPUB-DI)-2-(IBU)-acetylamino)-3-(3,4-methylenedioxyphenyl)propionamide
3-(2-(4PM-3-PUB-DI)-2-(IBU)-acetylamino)-3-(3,4-methylenedioxyphenyl)propanol
3-(2-(4PM-3-MPUB-DI)-2-(IBU)-acetylamino)-3-(3,4-methylenedioxyphenyl)propanol
3-(2-(4TM-3-PUB-DI)-2-(IBU)-acetylamino)-3-(3,4-methylenedioxyphenyl)propanol
3-(2-(4TM-3-MPUB-DI)-2-(IBU)-acetylamino)-3-(3,4-methylenedioxyphenyl)propanol
3-(2-(4OPM-3-PUB-DI)-2-(IBU)-acetylamino)-3-(3,4-methylenedioxyphenyl)propanol
3-(2-(4OPM-3-MPUB-DI)-2-(IBU)-acetylamino)-3-(3,4-methylenedioxyphenyl)propanol
3-(2-(4OTM-3-PUB-DI)-2-(IBU)-acetylamino)-3-(3,4-methylenedioxyphenyl)propanol
3-(2-(4OTM-3-MPUB-DI)-2-(IBU)-acetylamino)-3-(3,4-methylenedioxyphenyl)propanol
3-(2-(4PM-3-PUB-DI)-2-(IBU)-acetylamino)-3-(3,4-ethylenedioxyphenyl)propionic acid
3-(2-(4PM-3-MPUB-DI)-2-(IBU)-acetylamino)-3-(3,4-ethylenedioxyphenyl)propionic acid
3-(2-(4TM-3-PUB-DI)-2-(IBU)-acetylamino)-3-(3,4-ethylenedioxyphenyl)propionic acid
3-(2-(4TM-3-MPUB-DI)-2-(IBU)-acetylamino)-3-(3,4-ethylenedioxyphenyl)propionic acid
3-(2-(4OPM-3-PUB-DI)-2-(IBU)-acetylamino)-3-(3,4-ethylenedioxyphenyl)propionic acid
3-(2-(4OPM-3-MPUB-DI)-2-(IBU)-acetylamino)-3-(3,4-ethylenedioxyphenyl)propionic acid
3-(2-(4OTM-3-PUB-DI)-2-(IBU)-acetylamino)-3-(3,4-ethylenedioxyphenyl)propionic acid
3-(2-(4OTM-3-MPUB-DI)-2-(IBU)-acetylamino)-3-(3,4-ethylenedioxyphenyl)propionic acid
3-(2-(4PM-3-PUB-DI)-2-(IBU)-acetylamino)-3-(3,4-ethylenedioxyphenyl)propionamide
3-(2-(4PM-3-MPUB-DI)-2-(IBU)-acetylamino)-3-(3,4-ethylenedioxyphenyl)propionamide
3-(2-(4TM-3-PUB-DI)-2-(IBU)-acetylamino)-3-(3,4-ethylenedioxyphenyl)propionamide
3-(2-(4TM-3-MPUB-DI)-2-(IBU)-acetylamino)-3-(3,4-ethylenedioxyphenyl)propionamide
3-(2-(4OPM-3-PUB-DI)-2-(IBU)-acetylamino)-3-(3,4-ethylenedioxyphenyl)propionamide
3-(2-(4OPM-3-MPUB-DI)-2-(IBU)-acetylamino)-3-(3,4-ethylenedioxyphenyl)propionamide
3-(2-(4OTM-3-PUB-DI)-2-(IBU)-acetylamino)-3-(3,4-ethylenedioxyphenyl)propionamide
3-(2-(4OTM-3-MPUB-DI)-2-(IBU)-acetylamino)-3-(3,4-ethylenedioxyphenyl)propionamide
3-(2-(4PM-3-PUB-DI)-2-(IBU)-acetylamino)-3-(3,4-ethylenedioxyphenyl)propanol
3 (2-(4PM-3-MPUB-DI)-2-(IBU)-acetylamino)-3-(3,4-ethylenedioxyphenyl)propanol
3-(2-(4TM-3-PUB-DI)-2-(IBU)-acetylamino)-3-(3,4-ethylenedioxyphenyl)propanol
3-(2-(4TM-3-MPUB-DI)-2-(IBU)-acetylamino)-3-(3,4-ethylenedioxyphenyl)propanol
3-(2-(4OPM-3-PUB-DI)-2-(IBU)-acetylamino)-3-(3,4-ethylenedioxyphenyl)propanol
3-(2-(4OPM-3-MPUB-DI)-2-(IBU)-acetylamino)-3-(3,4-ethylenedioxyphenyl)propanol
3-(2-(4OTM-3-PUB-DI)-2-(IBU)-acetylamino)-3-(3,4-ethylenedioxyphenyl)propanol
3-(2-(4OTM-3-MPUB-DI)-2-(IBU)-acetylamino)-3-(3,4-ethylenedioxyphenyl)propanol
All abovementioned compounds are a subject of the present invention in all their stereoisomeric forms and in the form of mixtures thereof in all ratios. The compound 3-(2-(4,4-(3-oxopentamethylene)-3-(4-(3-(2-methylphenyl)ureido)benzyl)-2,5-dioxoimidazolidin-1-yl)-2-(2-methylpropyl)acetylamino)-3-(3,4-dimethoxyphenyl)propionamide mentioned above as an example is thus a subject of the invention, inter alia, in the form of (RS)-3-((RS)-2-(4,4-(3-oxopentamethylene)-3-(4-(3-(2-methylphenyl)ureido)benzyl)-2,5-dioxoimidazolidin-1-yl)-2-(2-methylpropyl)acetyl-amino)-3-(3,4-dimethoxyphenyl)propionamide, in the form of (S)-3-((S)-2-(4,4-(3-oxopentamethylene)-3-(4-(3-(2-methylphenyl)ureido)benzyl)-2,5-dioxoimidazolidin-1-yl)-2-(2-methylpropyl)acetylamino)-3-(3,4-dimethoxyphenyl)propionamide, in the form of (S)-3-((R)-2-(4,4-(3-oxopentamethylene)-3-(4-(3-(2-methylphenyl)ureido)benzyl)-2,5-dioxoimidazolidin-1-yl)-2-(2-methylpropyl)acetylamino)-3-(3,4-dimethoxyphenyl)propionamide, in the form of (R)-3-((S)-2-(4,4-(3-oxopentamethylene)-3-(4-(3-(2-methylphenyl)ureido)benzyl)-2,5-dioxoimidazolidin-1-yl)-2-(2-methylpropyl)acetylamino)-3-(3,4-dimethoxyphenyl)propionamide, in the form of (R)-3-((R)-2-(4,4-(3-oxopentamethylene)-3-(4-(3-(2-methylphenyl)ureido)benzyl)-2,5-dioxoimidazolidin-1-yl)-2-(2-methylpropyl)acetylamino)-3-(3,4-dimethoxyphenyl)propionamide, in the form of (S)-3-((RS)-2-(4,4-(3-oxopentamethylene)-3-(4-(3-(2-methylphenyl)ureido)benzyl)-2,5-dioxoimidazolidin-1-yl)-2-(2-methylpropyl)acetylamino)-3-(3,4-dimethoxyphenyl)propionamide, in the form of (R)-3-((RS)-2-(4,4-(3-oxopentamethylene)-3-(4-(3-(2-methylphenyl)ureido)benzyl)-2,5-dioxoimidazolidin-1-yl )-2-(2-methylpropyl)acetylamino)-3-(3,4-dimethoxyphenyl)propionamide, in the form of (RS)-3-((R)-2-(4,4-(3-oxopentamethylene)-3-(4-(3-(2-methylphenyl)ureido)benzyl)-2,5-dioxoimidazolidin-1-yl)-2-(2-methylpropyl)acetylamino)-3-(3,4-dimethoxyphenyl)propionamide and in the form of (RS)-3-((S)-2-(4,4-(3-oxopentamethylene)-3-(4-(3-(2-methylphenyl)ureido)-benzyl)-2,5-dioxoimidazolidin-1-yl)-2-(2-methylpropyl)acetylamino)-3-(3,4-dimethoxyphenyl)propionamide, and this applies expressly to all compounds mentioned. In another way of looking at the situation, with respect to the individual stereoisomers all compounds mentioned are a subject of the invention in the stereochemical arrangement which is shown in formula If, as well as in the arrangement which is shown in formula Ig, as well as in the arrangement which is shown in formula Ih, as well as in the arrangement which is shown in formula Ii, preferably in the stereochemical arrangement which is shown in formula If. Also all above-listed compounds are a subject of the invention in the form of their physiologically acceptable salts and in the form of their prodrugs and other physiologically acceptable derivatives, for example their esters.
The present invention furthermore expressly relates to all compounds analogous to the listed individual compounds which instead of the isobutyl-substituted acetylamino group contain a cyclopropylmethyl-substituted acetylamino group, and to all compounds analogous to the listed individual compounds which instead of the 4-(3-arylureido)benzyl group contain a 4-(3-arylureido)-3-methoxybenzyl group, and to all compounds analogous to the listed individual compounds which at the same time instead of the isobutyl-substituted acetylamino group contain a cyclopropylmethyl-substituted acetylamino group and instead of the 4-(3-arylureido)benzyl group contain a 4-(3-arylureido)-3-methoxybenzyl group, where also all these compounds are a subject of the present invention in all their stereoisomeric forms and in the form of mixtures thereof in all ratios and in the form of their physiologically acceptable salts and in the form of their prodrugs.
The compounds of the formula I can be prepared, for example, by condensation of a compound of the formula II 
with a compound of the formula III 
where, in the formulae II and III the groups X, W, V, E, R1 and R2 are defined as indicated above or also functional groups in these groups can be present in protected form or in the form of precursors, and where G is hydroxycarbonyl, (C1-C6)-alkoxycarbonyl or an activated carboxylic acid derivative such as an acid chloride or an active ester.
In the condensation of the compounds of the formulae II and III, usually it is necessary that a carboxylic acid group which is present but which is not involved in the condensation reaction is protected by a reversible protective group, for example as a suitable (C1-C6)-alkyl ester such as the tert-butyl ester or as a benzyl ester. If compounds of the formula I are to be prepared in which the group E is, for example, hydroxycarbonyl or a group which is to be prepared from a hydroxycarbonyl group, in the compounds of the formula III, for example, the group E can initially be a hydroxycarbonyl group which is present in protected form and then, after the condensation of the compounds of the formulae II and III, in one or more further steps, the hydroxycarbonyl group can be liberated or the desired final group E can be synthesized.
Precursors of functional groups are groups which can be converted into the desired functional group by the customary synthesis processes known to the person skilled in the art. For example, a cyano group which can be converted into an acid amide group or a carboxylic acid group by hydrolysis or can be converted into a tetrazole by reaction with an azide can be designated as a precursor for these groups. An alcohol group which can be oxidized to an aldehyde group can be designated as a precursor for this group. Examples of protective groups which are introduced into a molecule before carrying out a reaction or a reaction sequence and are later removed again have already been mentioned.
For the condensation of the compounds of the formulae II and III, the coupling methods of peptide chemistry which are well-known to the person skilled in the art are advantageously used (see, for example, Houben-Weyl, Methoden der Organischen Chemie, Volume 15/1 and 15/2, Georg Thieme Verlag, Stuttgart, 1974). Suitable condensing agents or coupling reagents are, for example, carbonyldiimidazole, carbodiimides such as dicyclohexylcarbodiimide (DCC) or diisopropylcarbodiimide, O-((cyano(ethoxycarbonyl)methylene)amino)-N,N,Nxe2x80x2,Nxe2x80x2-tetramethyluronium tetrafluoroborate (TOTU) or propylphosphonic anhydride (PPA). The condensations can be carried out under the standard conditions well-known to the person skilled in the art. In general, they are carried out in an inert solvent or diluent, for example in an aprotic solvent such as N,N-dimethylformamide (DMF), dimethyl sulfoxide (DMSO), N-methyl-2-pyrrolidone (NMP), tetrahydrofuran (THF) or dimethoxyethane (DME). Depending on the condensation carried out in the individual case, it may be advantageous to add a base such as a tertiary amine or auxiliary reagents, for example an N-hydroxy compound such as 1-hydroxybenzotriazole (HOBT). The working-up of the reaction mixture and a purification of the product can be carried out by customary standard processes. After the condensation, the protective groups present are removed in a suitable manner. For example, benzyl groups in benzyl esters can be removed by hydrogenation or protective groups of the tert-butyl type can be removed acidically. The compounds of the formula I can also be prepared, for example, by synthesizing the compounds stepwise on a solid phase according to customary methods, it being possible to introduce the individual structural elements of the molecule in different sequences.
The amino compounds of the formula III are commercially available or can be synthesized by or analogously to well-known standard processes from starting compounds which are commercially available or, in turn, are obtainable by or analogously to literature procedures. For example, optically active 3-substituted 3-aminopropionic acids of the formula III or their esters, preferably 3-phenyl-3-aminopropionic acid esters, can be prepared from the corresponding 3-substituted acrylic acids, which in turn are obtainable from the corresponding aldehydes. The 3-substituted acrylic acids are converted into the acid chlorides using oxalyl chloride, and the acid chlorides are converted into the esters using an alcohol, for example into the tert-butyl esters using tert-butanol. For the introduction of the amino group, the ester is then reacted with the lithium salt of an optically active amine, for example the lithium salt of (R)-(+)-N-benzyl-N-(1-phenylethyl)amine, and subsequently, in the 3-substituted tert-butyl 3-(N-benzyl-N-(1-phenylethyl)amino)propionate obtained, the benzyl group and the phenylethyl group are removed by catalytic hydrogenation. For the preparation of compounds of the formula III in which E is the hydroxymethyl group CH2OH or an etherified or esterified hydroxymethyl group, 3-substituted 3-aminopropanols or their esters or ethers which are obtainable from the 3-substituted 3-aminopropionic acids or their esters by reduction of the acid group (or of the ester group), for example from the ethyl ester or tert-butyl ester using lithium aluminum hydride or lithium aluminum hydride/aluminum trichloride, can be employed in the condensation reaction.
Compounds of the formula II can be prepared, for example, by first reacting compounds of the formula IV 
in a Bucherer reaction, for example with ammonium carbonate and potassium cyanide, to give compounds of the formula V 
where, in the formulae IV and V, the group X is defined as indicated above or a functional group can be present in protected form or in the form of a precursor. Compounds of the formula VI 
in which W, X and G are defined as indicated above or functional groups can be present in protected form or in the form of precursors, can then be obtained by reacting the compounds of the formula V, for example, with a first alkylating reagent of the formula LGxe2x80x94CH(G)xe2x80x94CH2xe2x80x94W which introduces the residue xe2x80x94CH(G)xe2x80x94CH2xe2x80x94W into the molecule. The reaction of compounds of the formula VI with a second alkylating reagent of the formula VIII 
in which V and R1 are defined as indicated above, then leads to the corresponding compounds of the formula II. The group LG is a nucleophilically substitutable leaving group, for example halogen such as chlorine or bromine, or sulfonyloxy such as tosyloxy, methylsulfonyloxy or trifluoromethylsulfonyloxy.
Compounds of the formula II can also be prepared, for example, by reacting a compound of the formula VI first with a reagent of the formula 4-(PGxe2x80x94NH)xe2x80x94C6VH3xe2x80x94CH2xe2x80x94LG, in which LG in turn is a nucleophilically substitutable leaving group and the group V in the 3-position is hydrogen or methoxy, to give a compound of the formula VIII 
where the meanings indicated above apply to G, V, W and X and PG is an amino protective group, for example tert-butoxycarbonyl or benzyloxycarbonyl. After removal of the protective group PG, the compounds of the formula II are obtained by reaction of the resulting amino group H2N with phenyl isocyanate or with 2-methylphenyl isocyanate. Like compounds of the formula VIII, also compounds can be prepared and employed in which the group PGxe2x80x94NHxe2x80x94 in the formula VIII is replaced by a group which is a precursor for an amino group and which is then converted into an amino group in a further reaction step. For example a compound of the formula VI can first be reacted with a nitro compound of the formula 4-O2Nxe2x80x94C6VH3xe2x80x94CH2xe2x80x94LG to give a compound corresponding to the compound of the formula VIII, then the nitro group can be converted into the amino group, for example by catalytic hydrogenation, and then the amino group can be converted into the desired compound of the formula II using phenyl isocyanate or 2-methylphenyl isocyanate.
In case a compound of the formula I is to be prepared in which one of the CH2 groups in the group X in the spiro-linked ring is replaced by a Cxe2x95x90O group, it is expedient first to protect this carbonyl group, for example as a ketal, and to carry out the Bucherer reaction with the protected compound of the formula IV, for example the monoketal of the cycloalkanedione. The alkylations of the protected compound of the formula V to give the compounds of the formulae VI and VII are then carried out as explained and thereafter, or otherwise at a later time during the synthesis, the carbonyl group in the group X is liberated again. In the case of a ketal protective group, the liberation of the protected carbonyl group can be carried out by treating with an acid analogously to literature processes.
In general, the individual steps in the preparation of the compounds of the formula I can be carried out according to or analogously to known methods familiar to the person skilled in the art. As already mentioned and as is known to the person skilled in the art, depending on the individual case it may be appropriate in all steps in the synthesis of the compounds of the formula I temporarily to block functional groups which could lead to side reactions or undesired reactions by a protective group strategy tailored to the synthesis problem.
Compounds of the formula I can also be obtained as follows. By reaction of N-substituted amino acids obtainable by standard processes or preferably of their esters, for example the methyl esters, ethyl esters, tert-butyl esters or benzyl esters, for example of compounds of the formula IX 
in which R1, V and X are defined as indicated above, with an isocyanate of the formula X 
for which the above definitions apply and which is obtainable according to standard processes from the corresponding compound which instead of the isocyanate group contains an H2N group, urea derivatives, for example of the formula XI 
for which the definitions indicated above apply, are obtained. The compounds of the formula XI can then be cyclized to the compounds of the formula I by heating with acid. The cyclization of the compounds of the formula XI to the compounds of the formula I can also be carried out by treatment with bases in inert solvents, for example by treating with sodium hydride in an aprotic solvent such as dimethylformamide. During the reaction, functional groups can be present in protected form.
Compounds of the formula I can also be obtained by reacting a compound of the formula IX with an isocyanate of the formula XII 
in which Q, for example, is an alkoxy group, for example a (C1-C4)-alkoxy group such as methoxy, ethoxy or tert-butoxy, or a (C6-C14)-aryl-(C1-C4)-alkoxy group, for example benzyloxy, and W has the meanings indicated above. In this case, a compound of the formula XIII is obtained 
in which X, W, V, Q and R1 are defined as indicated above, which is then cyclized under the influence of an acid or of a base, as described above for the cyclization of the compounds of the formula XI, to a compound of the formula XIV 
in which Q, W, V, X and R1 are defined as indicated above. In the compound of the formula XIV, it is then possible, for example by means of hydrolysis, to convert the group COxe2x80x94Q into the carboxylic acid group COOH. If the cyclization of the compound of the formula XII to the compound of the formula XIV is carried out using an acid, the conversion of the group COxe2x80x94Q into the group COOH can also be carried out simultaneously with the cyclization. By subsequent coupling with a compound of the formula III, as described above for the coupling of the compounds of the formulae II and III, a compound of the formula I is then obtained. In this synthesis process too, functional groups can be present in protected form or in the form of precursors.
A further method for the preparation of compounds of the formula I is, for example, the reaction of compounds of the formula XV 
for which the definitions indicated above apply, with phosgene or corresponding equivalents (analogously to S. Goldschmidt and M. Wick, Liebigs Ann. Chem. 575 (1952), 217 and C. Tropp, Chem. Ber. 61 (1928), 1431).
Compounds of the formula I can also be prepared by first coupling a compound of the formula XVI 
in which X has the meanings indicated above and PG is an amino protective group such as, for example, a benzyloxycarbonyl group, to a compound of the formula XVII 
in which Qxe2x80x2 is a protected carboxylic acid hydroxy group, for example an alkoxy group such as tert-butoxy, and W has the meanings indicated above, to give a compound of the formula XVIII 
in which X, W, PG and Qxe2x80x2 have the meanings indicated above. In the compound of the formula XVIII, it is then possible to remove the protective group PG from the amino group selectively, for example by hydrogenation in the case of a benzyloxycarbonyl group, and by introduction of a CO group a ring closure can be carried out to give a compound of the formula XIX 
in which X, W and Qxe2x80x2 have the meanings indicated above. For the introduction of the carbonyl group, it is possible to use, for example, phosgene or a phosgene equivalent (analogously to the reaction of the compounds of the formula XV illustrated above). An intermediate which can occur or can be specifically prepared in the conversion of the compound of the formula XVIII into the compound of the formula XIX is, for example, an isocyanate. The conversion of the compound of the formula XVIII into that of the formula XIX can be carried out in one or more steps. For example, the carbonyl group can first be introduced into the molecule and in a separate step the cyclization can then be carried out in the presence of a base such as sodium hydride, like the cyclizations described above. Compounds of the formula XVIII, in which PG is the benzyloxycarbonyl group, can also be converted directly into compounds of the formula XIX without an additional synthesis component such as phosgene being employed for the introduction of the carbonyl group. If compounds of the formula XVIII in which PG is benzyloxycarbonyl are treated with a base such as sodium hydride, the compounds of the formula XIX can be obtained directly.
The compounds of the formula XIX can then be alkylated on the NH group using a reagent of the formula VII, for example, as illustrated above for the compounds of the formula VI, and after conversion of the protected carboxylic acid group COxe2x80x94Qxe2x80x2 into the carboxylic acid group COOH, the desired compounds of the formula I can be synthesized as described above for the compounds of the formulae VI and II. In this synthesis process too, functional groups can be present in protected form or in the form of precursors.
Compounds of the formula I can furthermore be prepared by first reacting a compound of the formula XX 
in which X and Qxe2x80x2 have the meanings indicated above, with an isocyanate of the formula XII to give a compound of the formula XXI 
in which X, W, Q and Qxe2x80x2 have the meanings indicated above. The compound of the formula XXI is then cyclized by treating with a strong acid, for example half-concentrated hydrochloric acid, to a compound of the formula XXII. 
Compounds of the formula XXII can also be prepared by first preparing a compound of the formula XVIII in which X, W and Qxe2x80x2 have the meanings indicated and PG is an alkoxycarbonyl group such as (C1-C4)-alkoxycarbonyl, an arylalkoxycarbonyl group such as phenyl-(C1-C4)-alkoxycarbonyl, or an aryloxycarbonyl group such as phenyloxycarbonyl, converting it by liberating the protected carboxylic acid group COxe2x80x94Qxe2x80x2 into a compound of the formula XVIII in which COxe2x80x94Qxe2x80x2 is the free carboxylic acid group COxe2x80x94OH, PG is alkoxycarbonyl, arylalkoxycarbonyl or aryloxycarbonyl and X and W have the meanings indicated, and cyclizing this compound with a base such as, for example, sodium carbonate to the compound of the formula XXII.
Compounds of the formula IIa, 
in which R1, V, W and X have the meanings indicated above, can then be obtained by reacting the compounds of the formula XXII with an alkylating reagent of the formula VII in the presence of excess base, for example in the presence of an excess of n-butyllithium, and then acidifying. The 4-(3-arylureido)benzyl group can also be introduced into the compounds of the formula XXII stepwise, analogously to the preparation of the compounds of the formula VII and the compounds of the formula II obtained therefrom. If, in the compounds of the formula XXII, a CH2 group in the group X is replaced by a carbonyl group, it is expedient to protect this carbonyl group for the alkylation reactions to give the compounds of the formula IIa and to liberate it again after the alkylation, as has been explained above.
The compounds of the formula I in which E, for example, is hydroxycarbonyl or hydroxymethyl can be converted by standard processes into compounds of the formula I in which E has other meanings, or into other prodrugs or derivatives of the compounds of the formula I. Thus, for the preparation of esters the compounds of the formula I in which E is hydroxycarbonyl can be esterified with the corresponding alcohols, for example in the presence of a condensing reagent such as DCC, or the compounds of the formula I in which E is hydroxycarbonyl can be alkylated using alkyl halides such as alkyl chlorides or alkyl bromides, for example using chloroalkanamides to give compounds of the formula I in which E is R4R4Nxe2x80x94CO-alkoxy-COxe2x80x94, or with acyloxyalkyl halides to give compounds of the formula I in which E is acyloxyalkoxy-COxe2x80x94. Compounds of the formula I in which E is hydroxycarbonyl can be converted into amides using ammonia or organic amines in the presence of a condensing reagent. Compounds of the formula I in which E is COxe2x80x94NH2 can advantageously also be obtained on the solid phase, by coupling the compound in which E is COOH to Rink amide resin in the presence of a condensing agent such as TOTU and then removing it again from the resin using trifluoroacetic acid. Compounds of the formula I in which E is the hydroxymethyl group CH2OH can be etherified or esterified on the hydroxymethyl group according to standard processes. According to standard processes for the selective oxidation of alcohols to aldehydes, for example using sodium hypochlorite in the presence of 4-acetamido-2,2,6,6-tetramethylpiperidin-1-oxyl (4-acetamido-TEMPO), compounds of the formula I in which E is CH2OH can be converted into compounds of the formula I in which E is the aldehyde group COxe2x80x94H.
The compounds of the formula I are valuable pharmaceutical active compounds which are suitable, for example, for treating subjects in need of treatment. As used herein, xe2x80x9ctreatingxe2x80x9d or xe2x80x9ctreatmentxe2x80x9d includes the therapy and/or amelioration of a condition. However, xe2x80x9ctreatingxe2x80x9d or xe2x80x9ctreatmentxe2x80x9d also includes the prophylaxis or prevention of a condition. Such conditions include, but are not limited to diseases (or illnesses), such as, for example, inflammatory diseases, allergic diseases or asthma. In one embodiment, the invention relates to a method of treating a subject having asthma or an allergy, thereby preventing an acute asthma attack or allergic reaction. The compounds of the formula I and their physiologically acceptable salts and derivatives can be administered according to the invention to treat animals, preferably mammals, and most preferably to humans, as pharmaceuticals for therapy and/or prophylaxis. They can be administered on their own, in mixtures with one another or in the form of pharmaceutical preparations which allow enteral or parenteral use and which, as active constituent, contain an efficacious dose of at least one compound of the formula I and/or its physiologically acceptable salts and derivatives in addition to pharmaceutically innocuous vehicles and/or additives. The compounds of the formula I are administered in an amount effective for the treatment and/or prophylaxis of the condition.
The present invention therefore also relates to the compounds of the formula I and/or their physiologically acceptable salts and derivatives for use as pharmaceuticals, the use of the compounds of the formula I and/or their physiologically acceptable salts and derivatives for the production of pharmaceuticals for the treatment, such as therapy and prophylaxis, of the illnesses illustrated above and in the following, for example for the treatment, such as therapy and prophylaxis, of inflammatory diseases, and the use of the compounds of the formula I and/or their physiologically acceptable salts and derivatives in the treatment, such as therapy and prophylaxis, of these illnesses. The present invention furthermore relates to pharmaceutical preparations (or pharmaceutical compositions) which contain an efficacious dose of at least one compound of the formula I and/or its physiologically acceptable salts and derivatives and a pharmaceutically acceptable carrier, that is one or more pharmaceutically innocuous vehicles and/or additives.
The pharmaceuticals can be administered systemically or locally. They can be administered, for example, orally in the form of pills, tablets, film-coated tablets, sugar-coated tablets, granules, hard and soft gelatin capsules, powders, solutions, syrups, emulsions, suspensions and in other pharmaceutical forms. The administration can also be carried out vaginally or rectally, for example in the form of suppositories, or parenterally or by implantation, for example in the form of injection solutions or infusion solutions, microcapsules or rods, or topically or percutaneously, for example in the form of creams, ointments, powders, solutions, emulsions or tinctures, or in other ways, for example in the form of nasal sprays or aerosol mixtures. Parenteral administration of solutions can occur, for example, intravenously, intramuscularly, subcutaneously, intraarticularly, intrasynovially or in other ways.
The pharmaceutical preparations according to the invention are produced in a known manner, the compound or the compounds of the formula I and/or its physiologically acceptable salts and derivatives being mixed with pharmaceutically inert inorganic and/or organic vehicles and/or additives. For the production of pills, tablets, coated tablets and hard gelatin capsules, for example lactose, corn starch or derivatives thereof, talc, stearic acid or its salts, polyethylene glycols, etc. may be used. For soft gelatin capsules and suppositories, for example, fats, waxes, semisolid and liquid polyols, polyethylene glycols, natural or hardened oils etc. may be used. Suitable vehicles for the production of solutions, for example injection solutions, or of emulsions or syrups are, for example, water, alcohols, glycerol, diols, polyols, sucrose, invert sugar, glucose, vegetable oils etc. Suitable vehicles for microcapsules, implants or rods are, for example, copolymers of glycolic acid and lactic acid. The pharmaceutical preparations normally contain about 0.5 to about 90% by weight of the compounds of the formula I and/or their physiologically acceptable salts and derivatives. The amount of active compound of the formula I and/or its physiologically acceptable salts and derivatives in the pharmaceutical preparations is normally about 0.2 to about 1000 mg, preferably about 1 to about 500 mg, but depending on the nature of the pharmaceutical preparation the amount of the active compound can also be larger.
In addition to the active compounds and vehicles, the pharmaceutical preparations can additionally contain excipients or additives, for example fillers, disintegrants, binders, lubricants, wetting agents, stabilizing agents, emulsifiers, preservatives, sweeteners, colorants, flavorings, aromatizers, thickening agents, diluents, buffer substances, solvents, solubilizers, agents for achieving a depot effect, salts for changing the osmotic pressure, coating agents or antioxidants. They can also contain two or more compounds of the formula I and/or their physiologically acceptable salts and derivatives. Furthermore, in addition to at least one compound of the formula I and/or its physiologically acceptable salts and derivatives they can contain one or more other pharmaceutical active compounds, for example substances having antiinflammatory action.
If the compounds of the formula I or pharmaceutical preparations comprising them are administered as aerosols, for example as nasal aerosols or by inhalation, this can be carried out, for example, using a spray, a nebulizer, a pump nebulizer, an inhalation apparatus, a metered inhaler or a dry powder inhaler. Pharmaceutical forms for administration of the compounds of the formula I as an aerosol can be prepared by processes well-known to the person skilled in the art. For their preparation, for example, solutions or dispersions of the compounds of the formula I in water, water/alcohol mixtures or suitable saline solutions can be employed using customary additives, for example benzyl alcohol or other suitable preservatives, absorption enhancers for increasing the bioavailability, solubilizers, dispersants and others, and, if appropriate, customary propellants, for example chlorofluorohydrocarbons and/or fluorohydrocarbons.
Suitable other pharmaceutical active compounds which can be contained in addition to compounds of the formula I in the pharmaceutical preparations according to the invention, but with which the compounds of the formula I can also be combined in other ways in the context of a combination therapy or combination prophylaxis, are preferably such active compounds which are suitable for the therapy or prophylaxis of the illnesses mentioned above or in the following for whose therapy or prophylaxis the compounds of the formula I are suitable. Examples of classes of active compound of this type which may be mentioned are steroids, nonsteroidal antiinflammatory substances, nonsteroidal antiinflammatory acetic acid derivatives, nonsteroidal antiinflammatory propionic acid derivatives, nonsteroidal antiasthmatics, salicylic acid derivatives, pyrazolones, oxicams, leukotriene antagonists, inhibitors of leukotriene biosynthesis, cyclooxygenase inhibitors, cyclooxygenase-2 inhibitors, (COX-2 inhibitors), antihistamines, H1-histamine antagonists, nonsedating antihistamines, gold compounds, xcex22 agonists, anticholinergics, muscarine antagonists, antihyperlipidemics, antihypercholesterolemics, HMG-CoA reductase inhibitors, statins, nicotinic acid derivatives, immunosuppressants, cyclosporins, xcex2-interferons, tumor therapeutics, cytostatics, metastasis inhibitors, antimetabolites, 5-aminosalicylic acid derivatives, antidiabetics, insulins, sulfonylureas, biguanides, glitazones, xcex1-glucosidase inhibitors, and others. Examples of suitable active compounds which may be mentioned are acetylsalicylic acid, benorilate, sulfasalazine, phenylbutazone, oxyphenbutazone, metamizole, mofebutazone, feprazone, celecoxib, rofecoxib, diclofenac, fentiazac, sulindac, zomepirac, tolmetin, indometacin, acemetacin, ibuprofen, naproxen, carprofen, fenbufen, indoprofen, ketoprofen, pirprofen, tiaprofenic acid, diflunisal, flufenamic acid, meclofenamic acid, mefenamic acid, niflumic acid, tolfenamic acid, piroxicam, isoxicam, tenoxicam, nicotinic acid, prednisone, dexamethasone, hydrocortisone, methylprednisolone, betamethasone, beclomethasone, budesonide, montekulast, prankulast, zafirkulast, zileutone, ciclosporin, rapamycin, tacrolimus, methotrexate, 6-mercaptopurine, azathioprine, interferon-beta-1a, interferon-beta-1b, 5-aminosalicylic acid, leflunomide, D-penicillamine, chloroquine, glibenclamide, glimepiride, troglitazone, metformin, acarbose, atorvastatin, fluvastatin, lovastatin, simvastatin, pravastatin, colestipol, colestyramine, probucol, clofibrate, fenofibrate, bezafibrate, gemfibrozil, ipatropium bromide, clenbuterol, fenoterol, metaproterenol, pirbuterol, tulobuterol, salbutamol, salmeterol, terbutalin, isoetarine, ketotifen, ephedrine, oxitropium bromide, atropine, cromoglycic acid, theophylline, fexofenadine, terfenadine, cetirizine, dimetindene, diphenhydramine, diphenylpyraline, pheniramine, bromopheniramine, chloropheniramine, dexchloropheniramine, alimemazine, antazoline, astemizole, azatadine, clemastine, cyproheptadine, hydroxyzine, loratidine, mepyramine, promethazine, tripelennamine, triprolidine and others.
If compounds of the formula I and/or their physiologically acceptable salts or prodrugs are to be employed in a combination therapy or combination prophylaxis together with one or more other active compounds, this can be carried out as mentioned by administering all active compounds together in a single pharmaceutical preparation, for example a tablet or capsule. Pharmaceutical preparations of this type, for which all explanations above correspondingly apply, are expressly likewise a subject of the present invention. The amount of the active compounds in these pharmaceutical preparations is in general such that an efficacious amount of each active compound is present. A combination therapy or combination prophylaxis, however, can also be carried out by the active compounds being present in two or more separate pharmaceutical preparations which can be in a single pack or in two or more separate packs. The administration of the compounds of the formula I and/or their physiologically acceptable salts or products and the other active compounds can be carried out jointly or separately and can be carried out simultaneously or sequentially, in any order. The administration can also be carried out in different ways, for example one active compound can be administered orally and the other by injection, inhalation or topical application.
The compounds of the formula I have, for example, the ability to inhibit cell-cell interaction processes and cell-matrix interaction processes in which interactions between VLA-4 and its ligands play a role. The activity of the compounds of the formula I can be demonstrated, for example, in an assay in which the binding of cells which contain the VLA-4 receptor, for example of leukocytes, to ligands of this receptor, for example to VCAM-1 which advantageously can also be prepared for this purpose by genetic engineering, is measured. Details of such an assay are described below. In particular, the compounds of the formula I are able to inhibit the adhesion and the migration of leukocytes, for example the adhesion of leukocytes to endothelial cells whichxe2x80x94as explained abovexe2x80x94is controlled via the VCAM-1VLA-4 adhesion mechanism. Apart from as antiinflammatory substances, the compounds of the formula I and their physiologically acceptable salts and derivatives are therefore generally suitable for the therapy and prophylaxis of illnesses which are based on the interaction between the VLA-4 receptor and its ligands or can be affected by an inhibition of this interaction, and they are preferably suitable for the therapy and prophylaxis of illnesses which are at least partially caused by an undesired extent of leukocyte adhesion and/or leukocyte migration or are associated therewith, and for whose prevention, alleviation or cure the adhesion and/or migration of leukocytes should be decreased.
The present invention therefore also relates to the compounds of the formula I and their physiologically acceptable salts and derivatives for the inhibition of the adhesion and/or migration of leukocytes or for the inhibition of the VLA-4 receptor, and to the use of the compounds of the formula I for the production of pharmaceuticals for this, that is of pharmaceuticals for the therapy or prophylaxis of illnesses in which leukocyte adhesion and/or leukocyte migration exhibits an undesired extent, or for the therapy or prophylaxis of illnesses in which VLA-4-dependent adhesion processes play a part, and to the use of the compounds of the formula I and/or their physiologically acceptable salts and derivatives in the therapy and prophylaxis of illnesses of this type.
The compounds of the formula I can be employed as antiinflammatories in the case of inflammatory symptoms of very different causes in order to prevent, to decrease or to suppress the undesired or harmful consequences of inflammation. They are used, for example, for the therapy or prophylaxis of arthritis, of rheumatoid arthritis, of polyarthritis, of inflammatory bowel disease (ulcerative colitis), of systemic lupus erythematosus, for the therapy or prophylaxis of inflammatory disorders of the central nervous system such as, for example, of multiple sclerosis, or for the therapy or prophylaxis of asthma or of allergies, for example allergies of the delayed type (type IV allergy). They are furthermore suitable for the therapy or prophylaxis of cardiovascular disorders, of arteriosclerosis, of restenoses, of diabetes, of damage to organ transplants, of immune disorders, of autoimmune disorders, of tumor growth or tumor metastasis in various malignancies, of malaria as well as of further illnesses in which blocking of the integrin VLA-4 and/or influencing of the leukocyte activity appears appropriate for prevention, alleviation or cure.
The dose when using the compounds of the formula I can vary within wide limits, and as is customary and is known to the physician, it is to be tailored to the individual conditions in each individual case. It depends, for example, on the nature and severity of the illness to be treated, on the condition of the patient, on the compound employed or on whether an acute or chronic disease state is treated or prophylaxis is conducted or on whether further active compounds are administered in addition to the compounds of the formula I. In general, in the case of oral administration, a daily dose of about 0.01 to about 100 mg/kg, preferably about 0.1 to about 10 mg/kg (in each case mg of the compound per kg of body weight) is appropriate in an adult weighing about 75 kg to achieve effective results. In the case of intravenous administration, the daily dose is in general about 0.01 to about 50 mg/kg of body weight, preferably about 0.01 to about 10 mg/kg. The daily dose can be divided, especially when relatively large amounts are administered, into several, for example 2, 3 or 4, part administrations. If appropriate, depending on individual behavior, it may be necessary to deviate upward or downward from the daily dose indicated.
Apart from as pharmaceutical active compounds in human medicine and veterinary medicine, the compounds of the formula I and their salts and derivatives suitable for the use concerned can furthermore be employed for diagnostic purposes, for example in in-vitro diagnoses of cell samples or tissue samples, and as auxiliaries or as a scientific tool in biochemical investigations in which VLA-4 blocking or influencing of cell-cell or cell-matrix interactions is demanded. Furthermore, the compounds of the formula I and their salts can be used as intermediates for the preparation of other compounds, in particular of other pharmaceutical active compounds which are obtainable from compounds of the formula I, for example by modification or introduction of residues or functional groups, for example by esterification, reduction, oxidation or other conversions of functional groups.